Neuroactive steroids, compositions and uses thereof

ABSTRACT

Described herein are steroids of Formula (I):and pharmaceutically acceptable salts thereof, wherein R1, R2a, R2b, R3, R4, R5a, R5b, R6, and Z are as defined herein. Such compounds are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, convulsive disorders, disorders of memory and/or cognition, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes, and tinnitus.

RELATED APPLICATIONS

This application is a Divisional of Ser. No. 16/269,779, filed Feb. 7,2019, which is a Divisional of Ser. No. 15/319,503, filed Dec. 16, 2016,which is a National Stage Application under 35 U.S.C. § 371 ofInternational Application No. PCT/US2015/036500, filed Jun. 18, 2015,published as International Publication No. WO2015/195962 on Dec. 23,2015, which claims priority under 35 U.S.C. § 119(e) to U.S. ProvisionalApplication No. 62/014,010 filed Jun. 18, 2014, the entire contents ofwhich are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Brain excitability is defined as the level of arousal of an animal, acontinuum that ranges from coma to convulsions, and is regulated byvarious neurotransmitters. In general, neurotransmitters are responsiblefor regulating the conductance of ions across neuronal membranes. Atrest, the neuronal membrane possesses a potential (or membrane voltage)of approximately −70 mV, the cell interior being negative with respectto the cell exterior. The potential (voltage) is the result of ion (K⁺,Na⁺, Cl⁻, organic anions) balance across the neuronal semipermeablemembrane. Neurotransmitters are stored in presynaptic vesicles and arereleased under the influence of neuronal action potentials. Whenreleased into the synaptic cleft, an excitatory chemical transmittersuch as acetylcholine will cause membrane depolarization (change ofpotential from −70 mV to −50 mV). This effect is mediated bypostsynaptic nicotinic receptors which are stimulated by acetylcholineto increase membrane permeability to Na⁺ ions. The reduced membranepotential stimulates neuronal excitability in the form of a postsynapticaction potential.

In the case of the GABA receptor complex (GRC), the effect on brainexcitability is mediated by GABA, a neurotransmitter. GABA has aprofound influence on overall brain excitability because up to 40% ofthe neurons in the brain utilize GABA as a neurotransmitter. GABAregulates the excitability of individual neurons by regulating theconductance of chloride ions across the neuronal membrane. GABAinteracts with its recognition site on the GRC to facilitate the flow ofchloride ions down an electrochemical gradient of the GRC into the cell.An intracellular increase in the levels of this anion causeshyperpolarization of the transmembrane potential, rendering the neuronless susceptible to excitatory inputs (i.e., reduced neuronexcitability). In other words, the higher the chloride ion concentrationin the neuron, the lower the brain excitability (the level of arousal).

It is well-documented that the GRC is responsible for the mediation ofanxiety, seizure activity, and sedation. Thus, GABA and drugs that actlike GABA or facilitate the effects of GABA (e.g., the therapeuticallyuseful barbiturates and benzodiazepines (BZs), such as Valium®) producetheir therapeutically useful effects by interacting with specificregulatory sites on the GRC. Accumulated evidence has now indicated thatin addition to the benzodiazepine and barbiturate binding site, the GRCcontains a distinct site for neuroactive steroids (Lan, N. C. et al.,Neurochem. Res. 16:347-356 (1991)).

Neuroactive steroids can occur endogenously. The most potent endogenousneuroactive steroids are 3α-hydroxy-5-reduced pregnan-20-one and3α-21-dihydroxy-5-reduced pregnan-20-one, metabolites of hormonalsteroids progesterone and deoxycorticosterone, respectively. The abilityof these steroid metabolites to alter brain excitability was recognizedin 1986 (Majewska, M. D. et al., Science 232:1004-1007 (1986); Harrison,N. L. et al., J Pharmacol. Exp. Ther. 241:346-353 (1987)).

The ovarian hormone progesterone and its metabolites have beendemonstrated to have profound effects on brain excitability (Backstrom,T. et al., Acta Obstet. Gynecol. Scand. Suppl. 130:19-24 (1985); Pfaff,D. W and McEwen, B. S., Science 219:808-814 (1983); Gyermek et al., JMed Chem. 11: 117 (1968); Lambert, J. et al., Trends Pharmacol. Sci.8:224-227 (1987)). The levels of progesterone and its metabolites varywith the phases of the menstrual cycle. It has been well documented thatthe levels of progesterone and its metabolites decrease prior to theonset of menses. The monthly recurrence of certain physical symptomsprior to the onset of menses has also been well documented. Thesesymptoms, which have become associated with premenstrual syndrome (PMS),include stress, anxiety, and migraine headaches (Dalton, K.,Premenstrual Syndrome and Progesterone Therapy, 2nd edition, ChicagoYearbook, Chicago (1984)). Subjects with PMS have a monthly recurrenceof symptoms that are present in premenses and absent in postmenses.

In a similar fashion, a reduction in progesterone has also beentemporally correlated with an increase in seizure frequency in femaleepileptics, i.e., catamenial epilepsy (Laidlaw, J., Lancet, 1235-1237(1956)). A more direct correlation has been observed with a reduction inprogesterone metabolites (Rosciszewska et al., J. Neurol. Neurosurg.Psych. 49:47-51 (1986)). In addition, for subjects with primarygeneralized petit mal epilepsy, the temporal incidence of seizures hasbeen correlated with the incidence of the symptoms of premenstrualsyndrome (Backstrom, T. et al., J. Psychosom. Obstet. Gynaecol. 2:8-20(1983)). The steroid deoxycorticosterone has been found to be effectivein treating subjects with epileptic spells correlated with theirmenstrual cycles (Aird, R. B. and Gordan, G., J. Amer. Med. Soc.145:715-719 (1951)).

A syndrome also related to low progesterone levels is postnataldepression (PND). Immediately after birth, progesterone levels decreasedramatically leading to the onset of PND. The symptoms of PND range frommild depression to psychosis requiring hospitalization. PND is alsoassociated with severe anxiety and irritability. PND-associateddepression is not amenable to treatment by classic antidepressants, andwomen experiencing PND show an increased incidence of PMS (Dalton, K.,Premenstrual Syndrome and Progesterone Therapy, 2nd edition, ChicagoYearbook, Chicago (1984)).

Collectively, these observations imply a crucial role for progesteroneand deoxycorticosterone and more specifically their metabolites in thehomeostatic regulation of brain excitability, which is manifested as anincrease in seizure activity or symptoms associated with catamenialepilepsy, PMS, and PND. The correlation between reduced levels ofprogesterone and the symptoms associated with PMS, PND, and catamenialepilepsy (Backstrom, T. et al., J Psychosom.Obstet. Gynaecol. 2:8-20(1983)); Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2ndedition, Chicago Yearbook, Chicago (1984)) has prompted the use ofprogesterone in their treatment (Mattson et al., “Medroxyprogesteronetherapy of catamenial epilepsy,” in Advances in Epileptology: XVthEpilepsy International Symposium, Raven Press, New York (1984), pp.279-282, and Dalton, K., Premenstrual Syndrome and Progesterone Therapy,2nd edition, Chicago Yearbook, Chicago (1984)). However, progesterone isnot consistently effective in the treatment of the aforementionedsyndromes. For example, no dose-response relationship exists forprogesterone in the treatment of PMS (Maddocks et al., Obstet. Gynecol.154:573-581 (1986); Dennerstein et al., Brit. Med J290:16-17 (1986)).

New and improved neuroactive steroids are needed that act as modulatingagents for brain excitability, as well as agents for the prevention andtreatment of CNS-related diseases. The compounds, compositions, andmethods described herein are directed toward this end.

SUMMARY OF THE INVENTION

Provided herein are 19-substituted neuroactive steroids designed, forexample, to act as GABA modulators. In certain embodiments, suchcompounds are envisioned to be useful as therapeutic agents for theinducement of anesthesia and/or sedation in a subject. In someembodiments, such compounds are envisioned to be useful as therapeuticagents for treating a CNS-related disorder (e.g., sleep disorder, a mooddisorder, a schizophrenia spectrum disorder, a convulsive disorder, adisorder of memory and/or cognition, a movement disorder, a personalitydisorder, autism spectrum disorder, pain, traumatic brain injury, avascular disease, a substance abuse disorder and/or withdrawal syndrome,or tinnitus) in a subject in need (e.g., a subject with Rett syndrome,Fragile X syndrome, or Angelman syndrome).

In one aspect, the present invention provides compounds of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, carbocyclyl, or heterocyclyl; eachof R^(2a) and R^(2b) is independently hydrogen, C₁-C₆ alkyl, halo,cyano, —OR^(A), or —NR^(B)R^(C), or R^(2a) and R^(2b) together with thecarbon atom to which they are attached form a ring (e.g., a 3-7-memberedring, e.g., a 5-7-membered ring; a ring containing at least oneheteroatom, e.g., a nitrogen, oxygen, or sulfur atom); R³ is hydrogen,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, carbocyclyl, heterocyclyl,aryl, heteroaryl, —C(O)R^(A), —C(O)OR^(A), or —C(O)NR^(B)R^(C); R⁴ ishydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, carbocyclyl, or—OR^(A);

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond; wherein when the

between —CR⁶ and —CR^(5a)R^(5b) is a double bond, then one of R^(5a) orR^(5b) is absent; and when one of the

is a double bond, R⁶ is absent; Z is —CR^(7a)R^(7b)—, wherein each ofR^(7a) and R^(7b) is independently hydrogen or C₁-C₆ alkyl, or R^(7a)and R^(7b), together with the carbon atom to which they are attached,form a ring (e.g., carbocyclyl or heterocyclyl); each of R^(5a) andR^(5b) is independently absent, hydrogen, C₁-C₆ alkyl, or halo; R⁶ isabsent or hydrogen; R^(A) is hydrogen, C₁-C₆ alkyl, carbocyclyl,heterocyclyl, aryl, or heteroaryl; each of R^(B) and R^(C) isindependently hydrogen, C₁-C₆ alkyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, or taken together with the atom to which they are attachedform a ring (e.g., a 3-7-membered ring, e.g., a 5-7-membered ring; aring containing at least one heteroatom, e.g., a nitrogen, oxygen, orsulfur atom); or R^(D) is hydrogen, C₁-C₆ alkyl, carbocyclyl,heterocyclyl, aryl, or heteroaryl.

In one aspect, the present invention provides pharmaceuticalcompositions comprising a compound described herein, e.g., a compound ofFormula (I), or pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient.

In one aspect, the present invention provides a method for treating aCNS-related disorder in a subject in need thereof, comprisingadministering to the subject an effective amount of a compound describedherein, e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof. In some embodiments, the CNS-related disorderis a sleep disorder, a mood disorder, a schizophrenia spectrum disorder,a convulsive disorder, a disorder of memory and/or cognition, a movementdisorder, a personality disorder, a sleep disorder, autism spectrumdisorder, pain, seizure, status epilepticus, depression (e.g., postnataldepression, postpartum depression), traumatic brain injury, a vasculardisease, a substance abuse disorder and/or withdrawal syndrome, ortinnitus. In some embodiments, the compound is administered orally,subcutaneously, intravenously, or intramuscularly. In some embodiments,the compound is administered chronically.

In one aspect, the present invention provides a method for inducinganesthesia or sedation, comprising administering to the subject aneffective amount of a compound described herein, e.g., a compound ofFormula (I), or a pharmaceutically acceptable salt thereof.

Definitions Chemical Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in ThomasSorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various isomeric forms, e.g., enantiomers and/ordiastereomers. For example, the compounds described herein can be in theform of an individual enantiomer, diastereomer or geometric isomer, orcan be in the form of a mixture of stereoisomers, including racemicmixtures and mixtures enriched in one or more stereoisomer. Isomers canbe isolated from mixtures by methods known to those skilled in the art,including chiral high pressure liquid chromatography (HPLC) and theformation and crystallization of chiral salts; or preferred isomers canbe prepared by asymmetric syntheses. See, for example, Jacques et al.,Enantiomers, Racemates and Resolutions (Wiley Interscience, New York,1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistryof Carbon Compounds (McGraw-Hill, N Y, 1962); and Wilen, Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, IN 1972). The invention additionallyencompasses compounds described herein as individual isomerssubstantially free of other isomers, and alternatively, as mixtures ofvarious isomers.

As used herein a pure enantiomeric compound is substantially free fromother enantiomers or stereoisomers of the compound (i.e., inenantiomeric excess). In other words, an “S” form of the compound issubstantially free from the “R” form of the compound and is, thus, inenantiomeric excess of the “R” form. The term “enantiomerically pure” or“pure enantiomer” denotes that the compound comprises more than 75% byweight, more than 80% by weight, more than 85% by weight, more than 90%by weight, more than 91% by weight, more than 92% by weight, more than93% by weight, more than 94% by weight, more than 95% by weight, morethan 96% by weight, more than 97% by weight, more than 98% by weight,more than 98.5% by weight, more than 99% by weight, more than 99.2% byweight, more than 99.5% by weight, more than 99.6% by weight, more than99.7% by weight, more than 99.8% by weight or more than 99.9% by weight,of the enantiomer. In certain embodiments, the weights are based upontotal weight of all enantiomers or stereoisomers of the compound.

In the compositions provided herein, an enantiomerically pure compoundcan be present with other active or inactive ingredients. For example, apharmaceutical composition comprising enantiomerically pure R-compoundcan comprise, for example, about 90% excipient and about 10%enantiomerically pure R-compound. In certain embodiments, theenantiomerically pure R-compound in such compositions can, for example,comprise, at least about 95% by weight R-compound and at most about 5%by weight S-compound, by total weight of the compound. For example, apharmaceutical composition comprising enantiomerically pure S-compoundcan comprise, for example, about 90% excipient and about 10%enantiomerically pure S-compound. In certain embodiments, theenantiomerically pure S-compound in such compositions can, for example,comprise, at least about 95% by weight S-compound and at most about 5%by weight R-compound, by total weight of the compound. In certainembodiments, the active ingredient can be formulated with little or noexcipient or carrier.

Compound described herein may also comprise one or more isotopicsubstitutions. For example, H may be in any isotopic form, including ¹H,²H (D or deuterium), and ³H (T or tritium); C may be in any isotopicform, including ¹²C, ¹³C, and ¹⁴C; O may be in any isotopic form,including ¹⁶O and ¹⁸O; and the like.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

The following terms are intended to have the meanings presentedtherewith below and are useful in understanding the description andintended scope of the present invention. When describing the invention,which may include compounds, pharmaceutical compositions containing suchcompounds and methods of using such compounds and compositions, thefollowing terms, if present, have the following meanings unlessotherwise indicated. It should also be understood that when describedherein any of the moieties defined forth below may be substituted with avariety of substituents, and that the respective definitions areintended to include such substituted moieties within their scope as setout below. Unless otherwise stated, the term “substituted” is to bedefined as set out below. It should be further understood that the terms“groups” and “radicals” can be considered interchangeable when usedherein. The articles “a” and “an” may be used herein to refer to one orto more than one (i.e. at least one) of the grammatical objects of thearticle. By way of example “an analogue” means one analogue or more thanone analogue.

“Alkyl” refers to a radical of a straight-chain or branched saturatedhydrocarbon group having from 1 to 20 carbon atoms (“C₁₋₂₀ alkyl”). Insome embodiments, an alkyl group has 1 to 12 carbon atoms (“C₁₋₁₂alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms(“C₁₋₁₀ alkyl”). In some embodiments, an alkyl group has 1 to 9 carbonatoms (“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1 to 8carbon atoms (“C₁₋₈ alkyl”). In some embodiments, an alkyl group has 1to 7 carbon atoms (“C₁₋₇ alkyl”). In some embodiments, an alkyl grouphas 1 to 6 carbon atoms (“C₁₋₆ alkyl”, also referred to herein as “loweralkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms(“C₁₋₅ alkyl”). In some embodiments, an alkyl group has 1 to 4 carbonatoms (“C₁₋₄ alkyl”). In some embodiments, an alkyl group has 1 to 3carbon atoms (“C₁₋₃ alkyl”). In some embodiments, an alkyl group has 1to 2 carbon atoms (“C₁₋₂ alkyl”). In some embodiments, an alkyl grouphas 1 carbon atom (“C₁ alkyl”). In some embodiments, an alkyl group has2 to 6 carbon atoms (“C₂₋₆ alkyl”). Examples of C₁₋₆ alkyl groupsinclude methyl (C₁), ethyl (C₂), n-propyl (C₃), isopropyl (C₃), n-butyl(C₄), tert-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), n-pentyl (C₅),3-pentanyl (C₅), amyl (C₅), neopentyl (C₅), 3-methyl-2-butanyl (C₅),tertiary amyl (C₅), and n-hexyl (C₆). Additional examples of alkylgroups include n-heptyl (C₇), n-octyl (C₈) and the like. Unlessotherwise specified, each instance of an alkyl group is independentlyoptionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”)or substituted (a “substituted alkyl”) with one or more substituents;e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1substituent. In certain embodiments, the alkyl group is unsubstitutedC₁₋₁₀ alkyl (e.g., —CH₃). In certain embodiments, the alkyl group issubstituted C₁₋₁₀ alkyl. Common alkyl abbreviations include Me (—CH₃),Et (—CH₂CH₃), iPr (—CH(CH3)₂), nPr (—CH₂CH₂CH₃), n-Bu (—CH₂CH₂CH₂CH₃),or i-Bu (—CH₂CH(CH₃)₂).

As used herein, “alkylene,” “alkenylene,” and “alkynylene,” refer to adivalent radical of an alkyl, alkenyl, and alkynyl group, respectively.When a range or number of carbons is provided for a particular“alkylene,” “alkenylene,” and “alkynylene” group, it is understood thatthe range or number refers to the range or number of carbons in thelinear carbon divalent chain. “Alkylene,” “alkenylene,” and “alkynylene”groups may be substituted or unsubstituted with one or more substituentsas described herein.

“Alkylene” refers to an alkyl group wherein two hydrogens are removed toprovide a divalent radical, and which may be substituted orunsubstituted. Unsubstituted alkylene groups include, but are notlimited to, methylene (—CH₂—), ethylene (—CH₂CH₂—), propylene(—CH₂CH₂CH₂—), butylene (—CH₂CH₂CH₂CH₂—), pentylene (—CH₂CH₂CH₂CH₂CH₂—),hexylene (—CH₂CH₂CH₂CH₂CH₂CH₂—), and the like. Exemplary substitutedalkylene groups, e.g., substituted with one or more alkyl (methyl)groups, include but are not limited to, substituted methylene(—CH(CH₃)—, (—C(CH₃)₂—), substituted ethylene (—CH(CH₃)CH₂—,—CH₂CH(CH₃)—, —C(CH₃)₂CH₂—, —CH₂C(CH₃)₂—), substituted propylene(—CH(CH₃)CH₂CH₂—, —CH₂CH(CH₃)CH₂—, —CH₂CH₂CH(CH₃)—, —C(CH₃)₂CH₂CH₂—,—CH₂C(CH₃)₂CH₂—, —CH₂CH₂C(CH₃)₂—), and the like.

“Alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon doublebonds), and optionally one or more carbon-carbon triple bonds (e.g., 1,2, 3, or 4 carbon-carbon triple bonds) (“C₂₋₂₀ alkenyl”). In certainembodiments, alkenyl does not contain any triple bonds. In someembodiments, an alkenyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms(“C₂₋₉ alkenyl”). In some embodiments, an alkenyl group has 2 to 8carbon atoms (“C₂₋₈ alkenyl”). In some embodiments, an alkenyl group has2 to 7 carbon atoms (“C₂₋₇ alkenyl”). In some embodiments, an alkenylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, analkenyl group has 2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In someembodiments, an alkenyl group has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”).In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C₂₋₃alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C₂alkenyl”). The one or more carbon-carbon double bonds can be internal(such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples ofC₂₋₄ alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl(C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like.Examples of C₂₋₆ alkenyl groups include the aforementioned C₂₋₄ alkenylgroups as well as pentenyl (C), pentadienyl (C), hexenyl (C₆), and thelike. Additional examples of alkenyl include heptenyl (C₇), octenyl(C₅), octatrienyl (C₅), and the like. Unless otherwise specified, eachinstance of an alkenyl group is independently optionally substituted,i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a“substituted alkenyl”) with one or more substituents e.g., for instancefrom 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Incertain embodiments, the alkenyl group is unsubstituted C₂₋₁₀ alkenyl.In certain embodiments, the alkenyl group is substituted C₂₋₁₀ alkenyl.

“Alkenylene” refers to an alkenyl group wherein two hydrogens areremoved to provide a divalent radical, and which may be substituted orunsubstituted. Exemplary unsubstituted divalent alkenylene groupsinclude, but are not limited to, ethenylene (—CH═CH—) and propenylene(e.g., —CH═CHCH₂—, —CH₂—CH═CH—). Exemplary substituted alkenylenegroups, e.g., substituted with one or more alkyl (methyl) groups,include but are not limited to, substituted ethylene (—C(CH₃)═CH—,—CH═C(CH₃)—), substituted propylene (e.g., —C(CH₃)═CHCH₂—,—CH═C(CH₃)CH₂—, —CH═CHCH(CH₃)—, —CH═CHC(CH₃)₂—, —CH(CH₃)—CH═CH—,—C(CH₃)₂—CH═CH—, —CH₂—C(CH₃)═CH—, —CH₂—CH═C(CH₃)—), and the like.

“Alkynyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triplebonds), and optionally one or more carbon-carbon double bonds (e.g., 1,2, 3, or 4 carbon-carbon double bonds) (“C₂₋₂₀ alkynyl”). In certainembodiments, alkynyl does not contain any double bonds. In someembodiments, an alkynyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms(“C₂₋₉ alkynyl”). In some embodiments, an alkynyl group has 2 to 8carbon atoms (“C₂₋₈ alkynyl”). In some embodiments, an alkynyl group has2 to 7 carbon atoms (“C₂₋₇ alkynyl”). In some embodiments, an alkynylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkynyl”). In some embodiments, analkynyl group has 2 to 5 carbon atoms (“C₂₋₅ alkynyl”). In someembodiments, an alkynyl group has 2 to 4 carbon atoms (“C₂₋₄ alkynyl”).In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C₂₋₃alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C₂alkynyl”). The one or more carbon-carbon triple bonds can be internal(such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples ofC₂₋₄ alkynyl groups include, without limitation, ethynyl (C₂),1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), andthe like. Examples of C₂₋₆ alkenyl groups include the aforementionedC₂₋₄ alkynyl groups as well as pentynyl (C), hexynyl (C₆), and the like.Additional examples of alkynyl include heptynyl (C₇), octynyl (C₅), andthe like. Unless otherwise specified, each instance of an alkynyl groupis independently optionally substituted, i.e., unsubstituted (an“unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) withone or more substituents; e.g., for instance from 1 to 5 substituents, 1to 3 substituents, or 1 substituent. In certain embodiments, the alkynylgroup is unsubstituted C₂₋₁₀ alkynyl. In certain embodiments, thealkynyl group is substituted C₂₋₁₀ alkynyl.

“Alkynylene” refers to a linear alkynyl group wherein two hydrogens areremoved to provide a divalent radical, and which may be substituted orunsubstituted. Exemplary divalent alkynylene groups include, but are notlimited to, substituted or unsubstituted ethynylene, substituted orunsubstituted propynylene, and the like.

The term “heteroalkyl,” as used herein, refers to an alkyl group, asdefined herein, which further comprises 1 or more (e.g., 1, 2, 3, or 4)heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus)within the parent chain, wherein the one or more heteroatoms is insertedbetween adjacent carbon atoms within the parent carbon chain and/or oneor more heteroatoms is inserted between a carbon atom and the parentmolecule, i.e., between the point of attachment. In certain embodiments,a heteroalkyl group refers to a saturated group having from 1 to 10carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC₁₋₁₀ alkyl”). Insome embodiments, a heteroalkyl group is a saturated group having 1 to 9carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC₁₋₉ alkyl”). In someembodiments, a heteroalkyl group is a saturated group having 1 to 8carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC₁₋₈ alkyl”). In someembodiments, a heteroalkyl group is a saturated group having 1 to 7carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC₁₋₇ alkyl”). In someembodiments, a heteroalkyl group is a group having 1 to 6 carbon atomsand 1, 2, or 3 heteroatoms (“heteroC₁₋₆ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1or 2 heteroatoms (“heteroC₁₋₅ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms (“heteroC₁₋₄ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1heteroatom (“heteroC₁₋₃ alkyl”). In some embodiments, a heteroalkylgroup is a saturated group having 1 to 2 carbon atoms and 1 heteroatom(“heteroC₁₋₂ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 carbon atom and 1 heteroatom (“heteroC₁alkyl”). In some embodiments, a heteroalkyl group is a saturated grouphaving 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC₂₋₆ alkyl”).Unless otherwise specified, each instance of a heteroalkyl group isindependently unsubstituted (an “unsubstituted heteroalkyl”) orsubstituted (a “substituted heteroalkyl”) with one or more substituents.In certain embodiments, the heteroalkyl group is an unsubstitutedheteroC₁₋₁₀ alkyl. In certain embodiments, the heteroalkyl group is asubstituted heteroC₁₋₁₀ alkyl.

The term “heteroalkenyl,” as used herein, refers to an alkenyl group, asdefined herein, which further comprises one or more (e.g., 1, 2, 3, or4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon,phosphorus) wherein the one or more heteroatoms is inserted betweenadjacent carbon atoms within the parent carbon chain and/or one or moreheteroatoms is inserted between a carbon atom and the parent molecule,i.e., between the point of attachment. In certain embodiments, aheteroalkenyl group refers to a group having from 2 to 10 carbon atoms,at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC₂₋₁₀alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbonatoms at least one double bond, and 1, 2, 3, or 4 heteroatoms(“heteroC₂₋₉ alkenyl”). In some embodiments, a heteroalkenyl group has 2to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4heteroatoms (“heteroC₂₋₈ alkenyl”). In some embodiments, a heteroalkenylgroup has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or4 heteroatoms (“heteroC₂₋₇ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 6 carbon atoms, at least one double bond,and 1, 2, or 3 heteroatoms (“heteroC₂-alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 5 carbon atoms, at least one double bond,and 1 or 2 heteroatoms (“heteroC₂₋₅ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 4 carbon atoms, at least one double bond,and 1 or 2 heteroatoms (“heteroC₂₋₄ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 3 carbon atoms, at least one double bond,and 1 heteroatom (“heteroC₂₋₃ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 6 carbon atoms, at least one double bond,and 1 or 2 heteroatoms (“heteroC₂₋₆ alkenyl”). Unless otherwisespecified, each instance of a heteroalkenyl group is independentlyunsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a“substituted heteroalkenyl”) with one or more substituents. In certainembodiments, the heteroalkenyl group is an unsubstituted heteroC₂₋₁₀alkenyl. In certain embodiments, the heteroalkenyl group is asubstituted heteroC₂₋₁₀ alkenyl.

The term “heteroalkynyl,” as used herein, refers to an alkynyl group, asdefined herein, which further comprises one or more (e.g., 1, 2, 3, or4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon,phosphorus) wherein the one or more heteroatoms is inserted betweenadjacent carbon atoms within the parent carbon chain and/or one or moreheteroatoms is inserted between a carbon atom and the parent molecule,i.e., between the point of attachment. In certain embodiments, aheteroalkynyl group refers to a group having from 2 to 10 carbon atoms,at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC₂₋₁₀alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 9 carbonatoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms(“heteroC₂₋₉ alkynyl”). In some embodiments, a heteroalkynyl group has 2to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4heteroatoms (“heteroC₂₋₈ alkynyl”). In some embodiments, a heteroalkynylgroup has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or4 heteroatoms (“heteroC₂₋₇ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond,and 1, 2, or 3 heteroatoms (“heteroC₂₋₆ alkynyl”). In some embodiments,a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond,and 1 or 2 heteroatoms (“heteroC₂₋₅ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond,and 1 or 2 heteroatoms (“heteroC₂₋₄ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond,and 1 heteroatom (“heteroC₂₋₃ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond,and 1 or 2 heteroatoms (“heteroC₂₋₆ alkynyl”). Unless otherwisespecified, each instance of a heteroalkynyl group is independentlyunsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a“substituted heteroalkynyl”) with one or more substituents. In certainembodiments, the heteroalkynyl group is an unsubstituted heteroC₂₋₁₀alkynyl. In certain embodiments, the heteroalkynyl group is asubstituted heteroC₂₋₁₀ alkynyl.

As used herein, “alkylene,” “alkenylene,” “alkynylene,”“heteroalkylene,” “heteroalkenylene,” and “heteroalkynylene,” refer to adivalent radical of an alkyl, alkenyl, alkynyl group, heteroalkyl,heteroalkenyl, and heteroalkynyl group respectively. When a range ornumber of carbons is provided for a particular “alkylene,” “alkenylene,”“alkynylene,” “heteroalkylene,” “heteroalkenylene,” or“heteroalkynylene,” group, it is understood that the range or numberrefers to the range or number of carbons in the linear carbon divalentchain. “Alkylene,” “alkenylene,” “alkynylene,” “heteroalkylene,”“heteroalkenylene,” and “heteroalkynylene” groups may be substituted orunsubstituted with one or more substituents as described herein.

“Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclicor tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 πelectrons shared in a cyclic array) having 6-14 ring carbon atoms andzero heteroatoms provided in the aromatic ring system (“C₆₋₁₄ aryl”). Insome embodiments, an aryl group has six ring carbon atoms (“C₆ aryl”;e.g., phenyl). In some embodiments, an aryl group has ten ring carbonatoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). Insome embodiments, an aryl group has fourteen ring carbon atoms (“C₁₄aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein thearyl ring, as defined above, is fused with one or more carbocyclyl orheterocyclyl groups wherein the radical or point of attachment is on thearyl ring, and in such instances, the number of carbon atoms continue todesignate the number of carbon atoms in the aryl ring system. Typicalaryl groups include, but are not limited to, groups derived fromaceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene,benzene, chrysene, coronene, fluoranthene, fluorene, hexacene,hexaphene, hexalene, as-indacene, s-indacene, indane, indene,naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene,pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene,picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, andtrinaphthalene. Particularly aryl groups include phenyl, naphthyl,indenyl, and tetrahydronaphthyl. Unless otherwise specified, eachinstance of an aryl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted aryl”) or substituted (a “substitutedaryl”) with one or more substituents. In certain embodiments, the arylgroup is unsubstituted C₆₋₁₄ aryl. In certain embodiments, the arylgroup is substituted C₆₋₁₄ aryl.

In certain embodiments, an aryl group substituted with one or more ofgroups selected from halo, C₁-C₈ alkyl, C₁-C₈ haloalkyl, cyano, hydroxy,C₁-C₈ alkoxy, and amino.

Examples of Representative Substituted Aryls Include the Following

wherein one of R⁵⁶ and R⁵⁷ may be hydrogen and at least one of R⁵⁶ andR⁵⁷ is each independently selected from C₁-C₈ alkyl, C₁-C₈ haloalkyl,4-10 membered heterocyclyl, alkanoyl, C₁-C₈ alkoxy, heteroaryloxy,alkylamino, arylamino, heteroarylamino, NR⁵⁸COR⁵⁹, NR⁵⁸SOR⁵⁹NR⁵⁸SO₂RW⁹,COOalkyl, COOaryl, CONR⁵⁸R⁵⁹, CONR⁵⁸OR⁵⁹, NR⁵⁸R⁵⁹, SO₂NR⁵⁸R⁵⁹, S-alkyl,SOalkyl, SO₂alkyl, Saryl, SOaryl, SO₂aryl; or R⁵⁶ and R⁵⁷ may be joinedto form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms,optionally containing one or more heteroatoms selected from the group N,O, or S. R⁶⁰ and R⁶¹ are independently hydrogen, C₁-C₈ alkyl, C₁-C₄haloalkyl, C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₀ aryl,substituted C₆-C₁₀ aryl, 5-10 membered heteroaryl, or substituted 5-10membered heteroaryl.

Other representative aryl groups having a fused heterocyclyl groupinclude the following:

wherein each W is selected from C(R⁶⁶)₂, NR⁶⁶, O, and S; and each Y isselected from carbonyl, NR¹⁶, O and S; and R⁶ is independently hydrogen,C₁-C₈ alkyl, C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₀ aryl,and 5-10 membered heteroaryl.

“Fused aryl” refers to an aryl having two of its ring carbon in commonwith a second aryl or heteroaryl ring or with a carbocyclyl orheterocyclyl ring.

“Aralkyl” is a subset of alkyl and aryl, as defined herein, and refersto an optionally substituted alkyl group substituted by an optionallysubstituted aryl group.

“Heteroaryl” refers to a radical of a 5-10 membered monocyclic orbicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electronsshared in a cyclic array) having ring carbon atoms and 1-4 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-10 membered heteroaryl”). In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl bicyclic ring systems can includeone or more heteroatoms in one or both rings. “Heteroaryl” includes ringsystems wherein the heteroaryl ring, as defined above, is fused with oneor more carbocyclyl or heterocyclyl groups wherein the point ofattachment is on the heteroaryl ring, and in such instances, the numberof ring members continue to designate the number of ring members in theheteroaryl ring system. “Heteroaryl” also includes ring systems whereinthe heteroaryl ring, as defined above, is fused with one or more arylgroups wherein the point of attachment is either on the aryl orheteroaryl ring, and in such instances, the number of ring membersdesignates the number of ring members in the fused (aryl/heteroaryl)ring system. Bicyclic heteroaryl groups wherein one ring does notcontain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and thelike) the point of attachment can be on either ring, i.e., either thering bearing a heteroatom (e.g., 2-indolyl) or the ring that does notcontain a heteroatom (e.g., 5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unlessotherwise specified, each instance of a heteroaryl group isindependently optionally substituted, i.e., unsubstituted (an“unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”)with one or more substituents. In certain embodiments, the heteroarylgroup is unsubstituted 5-14 membered heteroaryl. In certain embodiments,the heteroaryl group is substituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing one heteroatominclude, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary5-membered heteroaryl groups containing two heteroatoms include, withoutlimitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, andisothiazolyl.

Exemplary 5-membered heteroaryl groups containing three heteroatomsinclude, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.Exemplary 5-membered heteroaryl groups containing four heteroatomsinclude, without limitation, tetrazolyl. Exemplary 6-membered heteroarylgroups containing one heteroatom include, without limitation, pyridinyl.Exemplary 6-membered heteroaryl groups containing two heteroatomsinclude, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.Exemplary 6-membered heteroaryl groups containing three or fourheteroatoms include, without limitation, triazinyl and tetrazinyl,respectively. Exemplary 7-membered heteroaryl groups containing oneheteroatom include, without limitation, azepinyl, oxepinyl, andthiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, withoutlimitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, andpurinyl. Exemplary 6,6-bicyclic heteroaryl groups include, withoutlimitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

Examples of representative heteroaryls include the following:

wherein each Y is selected from carbonyl, N, NR⁵, O, and S; and R⁵ isindependently hydrogen, C₁-C₈ alkyl, C₃-C₁₀ cycloalkyl, 4-10 memberedheterocyclyl, C₆-C₁₀ aryl, and 5-10 membered heteroaryl.

“Heteroaralkyl” is a subset of alkyl and heteroaryl, as defined herein,and refers to an optionally substituted alkyl group substituted by anoptionally substituted heteroaryl group.

“Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromaticcyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C₃₋₁₀carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. Insome embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms(“C₃₋₈ carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to6 ring carbon atoms (“C₃₋₆ carbocyclyl”). In some embodiments, acarbocyclyl group has 3 to 6 ring carbon atoms (“C₃₋₆ carbocyclyl”). Insome embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms(“C₅₋₁₀ carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groups include,without limitation, cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl(C₄), cyclobutenyl (C₄), cyclopentyl (C), cyclopentenyl (C), cyclohexyl(C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like. ExemplaryC₃₋₈ carbocyclyl groups include, without limitation, the aforementionedC₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇), cycloheptenyl (C₇),cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₅),cyclooctenyl (C₅), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl(C₅), and the like. Exemplary C₃₋₁₀ carbocyclyl groups include, withoutlimitation, the aforementioned C_(3-s) carbocyclyl groups as well ascyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl(C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀),spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged orspiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) andcan be saturated or can be partially unsaturated. “Carbocyclyl” alsoincludes ring systems wherein the carbocyclyl ring, as defined above, isfused with one or more aryl or heteroaryl groups wherein the point ofattachment is on the carbocyclyl ring, and in such instances, the numberof carbons continue to designate the number of carbons in thecarbocyclic ring system. Unless otherwise specified, each instance of acarbocyclyl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certainembodiments, the carbocyclyl group is unsubstituted C₃₋₁₀ carbocyclyl.In certain embodiments, the carbocyclyl group is a substituted C₃₋₁₀carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 10 ring carbon atoms (“C₃₋₁₀cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ringcarbon atoms (“C₃₋₈ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 6 ring carbon atoms (“C₃₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C₅₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ cycloalkyl”). Examples of C₅₋₆ cycloalkyl groupsinclude cyclopentyl (C₅) and cyclohexyl (C₅). Examples of C₃₋₆cycloalkyl groups include the aforementioned C₅₋₆ cycloalkyl groups aswell as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C₃₋₈cycloalkyl groups include the aforementioned C₃₋₆ cycloalkyl groups aswell as cycloheptyl (C₇) and cyclooctyl (C₅). Unless otherwisespecified, each instance of a cycloalkyl group is independentlyunsubstituted (an “unsubstituted cycloalkyl”) or substituted (a“substituted cycloalkyl”) with one or more substituents. In certainembodiments, the cycloalkyl group is unsubstituted C₃₋₁₀ cycloalkyl. Incertain embodiments, the cycloalkyl group is substituted C₃₋₁₀cycloalkyl.

“Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to10-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 memberedheterocyclyl”). In heterocyclyl groups that contain one or more nitrogenatoms, the point of attachment can be a carbon or nitrogen atom, asvalency permits. A heterocyclyl group can either be monocyclic(“monocyclic heterocyclyl”) or a fused, bridged or spiro ring systemsuch as a bicyclic system (“bicyclic heterocyclyl”), and can besaturated or can be partially unsaturated. Heterocyclyl bicyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclyl ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclylring, or ring systems wherein the heterocyclyl ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclyl ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclyl ring system. Unless otherwise specified, eachinstance of heterocyclyl is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a“substituted heterocyclyl”) with one or more substituents. In certainembodiments, the heterocyclyl group is unsubstituted 3-10 memberedheterocyclyl. In certain embodiments, the heterocyclyl group issubstituted 3-10 membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 memberedheterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8membered non-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-6 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-6 membered heterocyclyl”). In some embodiments, the 5-6 memberedheterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen,and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2ring heteroatoms selected from nitrogen, oxygen, and sulfur. In someembodiments, the 5-6 membered heterocyclyl has one ring heteroatomselected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing one heteroatominclude, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary4-membered heterocyclyl groups containing one heteroatom include,without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary5-membered heterocyclyl groups containing one heteroatom include,without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyland pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, dioxolanyl,oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-memberedheterocyclyl groups containing three heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclyl groups containing one heteroatom include,without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl,and thianyl. Exemplary 6-membered heterocyclyl groups containing twoheteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containingtwo heteroatoms include, without limitation, triazinanyl. Exemplary7-membered heterocyclyl groups containing one heteroatom include,without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary8-membered heterocyclyl groups containing one heteroatom include,without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred toherein as a 5,6-bicyclic heterocyclic ring) include, without limitation,indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groupsfused to an aryl ring (also referred to herein as a 6,6-bicyclicheterocyclic ring) include, without limitation, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and the like.

Particular examples of heterocyclyl groups are shown in the followingillustrative examples:

wherein each W is selected from CR⁶⁷, C(R⁶⁷)₂, NR⁶⁷, O, and S; and eachY is selected from NR⁶⁷, 0, and S; and R⁷ is independently hydrogen,C₁-C₈ alkyl, C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₀ aryl,5-10 membered heteroaryl. These heterocyclyl rings may be optionallysubstituted with one or more groups selected from the group consistingof acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl,alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (carbamoylor amido), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl,aryloxy, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, keto,nitro, thiol, —S-alkyl, —S-aryl, —S(O)-alkyl, —S(O)-aryl, —S(O)₂-alkyl,and —S(O)₂-aryl. Substituting groups include carbonyl or thiocarbonylwhich provide, for example, lactam and urea derivatives.

“Hetero” when used to describe a compound or a group present on acompound means that one or more carbon atoms in the compound or grouphave been replaced by a nitrogen, oxygen, or sulfur heteroatom. Heteromay be applied to any of the hydrocarbyl groups described above such asalkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g.,heteroaryl, cycloalkenyl, e.g., cycloheteroalkenyl, and the like havingfrom 1 to 5, and particularly from 1 to 3 heteroatoms.

“Acyl” refers to a radical —C(O)R²⁰, where R²⁰ is hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl, asdefined herein. “Alkanoyl” is an acyl group wherein R²⁰ is a group otherthan hydrogen. Representative acyl groups include, but are not limitedto, formyl (—CHO), acetyl (—C(═O)CH₃), cyclohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl (—C(═O)Ph), benzylcarbonyl(—C(═O)CH₂Ph), —C(O)—C₁-C₈ alkyl, —C(O)—(CH₂)_(t)(C₆-C₁₀ aryl),—C(O)—(CH₂)_(t)(5-10 membered heteroaryl), —C(O)—(CH₂)_(t)(C₃-C₁₀cycloalkyl), and —C(O)—(CH₂)_(t)(4-10 membered heterocyclyl), wherein tis an integer from 0 to 4. In certain embodiments, R²¹ is C₁-C₈ alkyl,substituted with halo or hydroxy; or C₃-C₁₀ cycloalkyl, 4-10 memberedheterocyclyl, C₆-C₁₀ aryl, arylalkyl, 5-10 membered heteroaryl orheteroarylalkyl, each of which is substituted with unsubstituted C₁-C₄alkyl, halo, unsubstituted C₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl,unsubstituted C₁-C₄ hydroxyalkyl, or unsubstituted C₁-C₄ haloalkoxy orhydroxy.

“Acylamino” refers to a radical —NR²²C(O)R²³, where each instance of R²²and R²³ is independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, as defined herein, or R²² is anamino protecting group. Exemplary “acylamino” groups include, but arenot limited to, formylamino, acetylamino, cyclohexylcarbonylamino,cyclohexylmethyl-carbonylamino, benzoylamino and benzylcarbonylamino.Particular exemplary “acylamino” groups are —NR²⁴C(O)—C₁-C₈ alkyl,—NR²⁴C(O)—(CH₂)_(t)(C₆-C₁₀ aryl), —NR²⁴C(O)—(CH₂)_(t)(5-10 memberedheteroaryl), —NR²⁴C(O)—(CH₂)_(t)(C₃-C₁₀ cycloalkyl), and—NR²⁴C(O)—(CH₂)_(t)(4-10 membered heterocyclyl), wherein t is an integerfrom 0 to 4, and each R²⁴ independently represents H or C₁-C₈ alkyl. Incertain embodiments, R²⁵ is H, C₁-C₈ alkyl, substituted with halo orhydroxy; C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₀ aryl,arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which issubstituted with unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl,or unsubstituted C₁-C₄ haloalkoxy or hydroxy; and R²⁶ is H, C₁-C₈ alkyl,substituted with halo or hydroxy; C₃-C₁₀ cycloalkyl, 4-10 memberedheterocyclyl, C₆-C₁₀ aryl, arylalkyl, 5-10 membered heteroaryl orheteroarylalkyl, each of which is substituted with unsubstituted C₁-C₄alkyl, halo, unsubstituted C₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl,unsubstituted C₁-C₄ hydroxyalkyl, or unsubstituted C₁-C₄ haloalkoxy orhydroxyl; provided at least one of R²⁵ and R²⁶ is other than H.

“Acyloxy” refers to a radical —OC(O)R²⁷, where R²⁷ is hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl, as defined herein. Representative examples include, but arenot limited to, formyl, acetyl, cyclohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl and benzylcarbonyl. In certainembodiments, R²⁸ is C₁-C₈ alkyl, substituted with halo or hydroxy;C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₀ aryl, arylalkyl,5-10 membered heteroaryl or heteroarylalkyl, each of which issubstituted with unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl,or unsubstituted C₁-C₄ haloalkoxy or hydroxy.

“Alkoxy” refers to the group —OR²⁹ where R²⁹ is substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl. Particular alkoxygroups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6carbon atoms. Further particular alkoxy groups have between 1 and 4carbon atoms.

In certain embodiments, R²⁹ is a group that has 1 or more substituents,for instance from 1 to 5 substituents, and particularly from 1 to 3substituents, in particular 1 substituent, selected from the groupconsisting of amino, substituted amino, C₆-C₁₀ aryl, aryloxy, carboxyl,cyano, C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol,alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—. Exemplary‘substituted alkoxy’ groups include, but are not limited to,—O—(CH₂)_(t)(C₆-C₁₀ aryl), —O—(CH₂)_(t)(5-10 membered heteroaryl),—O—(CH₂)_(t)(C₃-C₁₀ cycloalkyl), and —O—(CH₂)_(t)(4-10 memberedheterocyclyl), wherein t is an integer from 0 to 4 and any aryl,heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves besubstituted by unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl,or unsubstituted C₁-C₄ haloalkoxy or hydroxy. Particular exemplary‘substituted alkoxy’ groups are —OCF₃, —OCH₂CF₃, —OCH₂Ph,—OCH₂-cyclopropyl, —OCH₂CH₂OH, and —OCH₂CH₂NMe₂.

“Amino” refers to the radical —NH₂.

“Substituted amino” refers to an amino group of the formula —N(R³⁸)₂wherein R³⁸ is hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, or an amino protecting group, wherein at leastone of R³⁸ is not a hydrogen. In certain embodiments, each R³⁸ isindependently selected from hydrogen, C₁-C₈ alkyl, C₃-C₈ alkenyl, C₃-C₈alkynyl, C₆-C₁₀ aryl, 5-10 membered heteroaryl, 4-10 memberedheterocyclyl, or C₃-C₁₀ cycloalkyl; or C₁-C₈ alkyl, substituted withhalo or hydroxy; C₃-C₈ alkenyl, substituted with halo or hydroxy; C₃-C₈alkynyl, substituted with halo or hydroxy, or —(CH₂)_(t)(C₆-C₁₀ aryl),—(CH₂)_(t)(5-10 membered heteroaryl), —(CH₂)_(t)(C₃-C₁₀ cycloalkyl), or—(CH₂)_(t)(4-10 membered heterocyclyl), wherein t is an integer between0 and 8, each of which is substituted by unsubstituted C₁-C₄ alkyl,halo, unsubstituted C₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl,unsubstituted C₁-C₄ hydroxyalkyl, or unsubstituted C₁-C₄ haloalkoxy orhydroxy; or both R³⁸ groups are joined to form an alkylene group.

Exemplary “substituted amino” groups include, but are not limited to,—NR³⁹—C₁-C₅ alkyl, —NR³⁹—(CH₂)_(t)(C₆-C₁₀ aryl), —NR³⁹—(CH₂)_(t)(5-10membered heteroaryl), —NR³⁹—(CH₂)_(t)(C₃-C₁₀ cycloalkyl), and—NR³⁹—(CH₂)_(t)(4-10 membered heterocyclyl), wherein t is an integerfrom 0 to 4, for instance 1 or 2, each R³⁹ independently represents H orC₁-C₈ alkyl; and any alkyl groups present, may themselves be substitutedby halo, substituted or unsubstituted amino, or hydroxy; and any aryl,heteroaryl, cycloalkyl, or heterocyclyl groups present, may themselvesbe substituted by unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl,or unsubstituted C₁-C₄ haloalkoxy or hydroxy. For the avoidance of doubtthe term ‘substituted amino’ includes the groups alkylamino, substitutedalkylamino, alkylarylamino, substituted alkylarylamino, arylamino,substituted arylamino, dialkylamino, and substituted dialkylamino asdefined below. Substituted amino encompasses both monosubstituted aminoand disubstituted amino groups.

“Azido” refers to the radical —N₃.

“Carbamoyl” or “amido” refers to the radical —C(O)NH₂.

“Substituted carbamoyl” or “substituted amido” refers to the radical—C(O)N(R⁶²)₂ wherein each R⁶² is independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, or an amino protectinggroup, wherein at least one of R⁶² is not a hydrogen. In certainembodiments, R⁶² is selected from H, C₁-C₈ alkyl, C₃-C₁₀ cycloalkyl,4-10 membered heterocyclyl, C₆-C₁₀ aryl, aralkyl, 5-10 memberedheteroaryl, and heteroaralkyl; or C₁-C₈ alkyl substituted with halo orhydroxy; or C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₀ aryl,aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, each of which issubstituted by unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl,or unsubstituted C₁-C₄ haloalkoxy or hydroxy; provided that at least oneR⁶² is other than H.

Exemplary “substituted carbamoyl” groups include, but are not limitedto, —C(O) NR⁶⁴—C₁-C₈ alkyl, —C(O)NR⁶⁴—(CH₂)_(t)(C₆-C₁₀ aryl),—C(O)N⁶⁴—(CH₂)_(t)(5-10 membered heteroaryl), —C(O)NR⁴—(CH₂)_(t)(C₃-C₁₀cycloalkyl), and —C(O)NR⁶⁴—(CH₂)_(t)(4-10 membered heterocyclyl),wherein t is an integer from 0 to 4, each R⁶⁴ independently represents Hor C₁-C₈ alkyl and any aryl, heteroaryl, cycloalkyl or heterocyclylgroups present, may themselves be substituted by unsubstituted C₁-C₄alkyl, halo, unsubstituted C₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl,unsubstituted C₁-C₄ hydroxyalkyl, or unsubstituted C₁-C₄ haloalkoxy orhydroxy.

“Carboxy” refers to the radical —C(O)OH.

“Cyano” refers to the radical —CN.

“Halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), andiodo (I). In certain embodiments, the halo group is either fluoro orchloro.

“Hydroxy” refers to the radical —OH.

“Nitro” refers to the radical —NO₂.

“Cycloalkylalkyl” refers to an alkyl radical in which the alkyl group issubstituted with a cycloalkyl group. Typical cycloalkylalkyl groupsinclude, but are not limited to, cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl,cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl,cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl, and the like.

“Heterocyclylalkyl” refers to an alkyl radical in which the alkyl groupis substituted with a heterocyclyl group. Typical heterocyclylalkylgroups include, but are not limited to, pyrrolidinylmethyl,piperidinylmethyl, piperazinylmethyl, morpholinylmethyl,pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl,and the like.

“Cycloalkenyl” refers to substituted or unsubstituted carbocyclyl grouphaving from 3 to 10 carbon atoms and having a single cyclic ring ormultiple condensed rings, including fused and bridged ring systems andhaving at least one and particularly from 1 to 2 sites of olefinicunsaturation. Such cycloalkenyl groups include, by way of example,single ring structures such as cyclohexenyl, cyclopentenyl,cyclopropenyl, and the like.

“Fused cycloalkenyl” refers to a cycloalkenyl having two of its ringcarbon atoms in common with a second aliphatic or aromatic ring andhaving its olefinic unsaturation located to impart aromaticity to thecycloalkenyl ring.

“Ethylene” refers to substituted or unsubstituted —(C—C)—.

“Ethenyl” refers to substituted or unsubstituted —(C═C)—.

“Ethynyl” refers to —(C═C)—.

“Nitrogen-containing heterocyclyl” group means a 4- to 7-memberednon-aromatic cyclic group containing at least one nitrogen atom, forexample, but without limitation, morpholine, piperidine (e.g.2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g.2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline,imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazines such as N-methyl piperazine. Particular examples includeazetidine, piperidone and piperazone.

“Thioketo” refers to the group ═S.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylgroups, as defined herein, are optionally substituted (e.g.,“substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted”alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or“unsubstituted” carbocyclyl, “substituted” or “unsubstituted”heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or“unsubstituted” heteroaryl group). In general, the term “substituted”,whether preceded by the term “optionally” or not, means that at leastone hydrogen present on a group (e.g., a carbon or nitrogen atom) isreplaced with a permissible substituent, e.g., a substituent which uponsubstitution results in a stable compound, e.g., a compound which doesnot spontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction. Unless otherwise indicated,a “substituted” group has a substituent at one or more substitutablepositions of the group, and when more than one position in any givenstructure is substituted, the substituent is either the same ordifferent at each position. The term “substituted” is contemplated toinclude substitution with all permissible substituents of organiccompounds, any of the substituents described herein that results in theformation of a stable compound. For purposes of this invention,heteroatoms such as nitrogen may have hydrogen substituents and/or anysuitable substituent as described herein which satisfy the valencies ofthe heteroatoms and results in the formation of a stable moiety.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa),—SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(O)R^(aa), e.g., —S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃,—OSi(R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa),—SC(═S)SR^(aa), —SC(═O)SR^(aa), —OC(═O)SR^(aa), —SC(═O)OR^(aa),—SC(═O)R^(aa), —P(═O)₂R^(aa), —OP(═O)₂R^(aa), —P(═O)(R^(aa))₂,—OP(═O)(R^(aa))₂, —OP(═O)(OR^(C))₂, —P(═O)₂N(R^(bb))₂,—OP(═O)₂N(R^(bb))₂, —P(═O)(NR^(bb))₂, —OP(═O)(NR^(bb))₂,—NR^(bb)P(═O)(OR^(cc))₂, —NR^(bb)P(═O)(NR^(bb))₂, —P(R^(cc))₂,—P(R^(cc))₃, —OP(R^(cc))₂, —OP(R^(cc))₃, —B(R^(aa))₂, —B(OR^(cc))₂,—BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(aa) groups;

-   -   or two geminal hydrogens on a carbon atom are replaced with the        group ═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa),        ═NNR^(bb)C(═O)OR^(aa), ═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or        ═NOR^(cc);    -   each instance of R^(a) is, independently, selected from C₁₋₁₀        alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀        carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14        membered heteroaryl, or two R^(aa) groups are joined to form a        3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,        wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,        aryl, and heteroaryl is independently substituted with 0, 1, 2,        3, 4, or 5 R^(aa) groups;    -   each instance of R^(bb) is, independently, selected from        hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),        —C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(cc))OR^(aa),        —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),        —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),        —P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂,        —P(═O)(NR^(cc))₂, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀        alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered        heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or two        R^(bb) groups are joined to form a 3-14 membered heterocyclyl or        5-14 membered heteroaryl ring, wherein each alkyl, alkenyl,        alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is        independently substituted with 0, 1, 2, 3, 4, or 5 R^(aa)        groups;    -   each instance of R^(cc) is, independently, selected from        hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀        alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄        aryl, and 5-14 membered heteroaryl, or two R^(cc) groups are        joined to form a 3-14 membered heterocyclyl or 5-14 membered        heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,        carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently        substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;    -   each instance of R^(aa) is, independently, selected from        halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee),        —ON(R^(ff))₂, —N(R^(ff))₂, —N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff),        —SH, —SR^(ee), —SSR^(ee), —C(═O)R^(ee), —CO₂H, —CO₂R^(ee),        —OC(═O)R^(ee), —OCO₂R^(ee), —C(═O)N(R′)₂, —OC(═O)N(R′)₂,        —NR^(ff)C(═O)R^(ee), —NR^(ff)CO₂R^(ee), —NR^(ff)C(═O)N(R′)₂,        —C(═NR^(ff))OR^(ee), —OC(═NR⁷)R^(ee), —OC(═NR^(ff))OR^(ee),        —C(═NR^(ff))N(R^(ff))₂, —OC(═NR^(ff))N(R^(ff))₂,        —NR^(ff)C(═NR^(ff))N(R^(ff))₂, —NR^(ff)SO₂R^(ee), —SO₂N(Rf)₂,        —SO₂R^(cc), —SO₂OR^(ee), —OSO₂R^(ee), —S(O)R^(ee), e.g.,        —S(═O)R^(cc), —Si(R^(ee))₃, —OSi(R^(ee))₃, —C(═S)N(R^(ff))₂,        —C(═O)SR^(ee), —C(═S)SR^(ee), —SC(═S)SR^(ee), —P(═O)₂R^(ee),        —P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂, —OP(═O)(OR^(ee))₂, C₁_alkyl,        C₁_perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl,        3-10 membered heterocyclyl, C₆₋₁₀ aryl, 5-10 membered        heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,        heterocyclyl, aryl, and heteroaryl is independently substituted        with 0, 1, 2, 3, 4, or 5 R^(gg) groups, or two geminal R^(aa)        substituents can be joined to form ═O or ═S;    -   each instance of R^(ee) is, independently, selected from C₁₋₆        alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀        carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, and 3-10        membered heteroaryl, wherein each alkyl, alkenyl, alkynyl,        carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently        substituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups;    -   each instance of R^(ff) is, independently, selected from        hydrogen, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀        aryl and 5-10 membered heteroaryl, or two R^(ff) groups are        joined to form a 3-14 membered heterocyclyl or 5-14 membered        heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,        carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently        substituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups; and    -   each instance of R^(gg) is, independently, halogen, —CN, —NO₂,        —N₃, —SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆        alkyl)₂, —N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆        alkyl)⁺X⁻, —NH₃ ⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆        alkyl), —NH(OH), —SH, —SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆        alkyl), —CO₂H, —CO₂(C₁₋₆ alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆        alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆ alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl),        —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)C(═O)(C₁₋₆ alkyl),        —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂, —NHC(═O)NH(C₁₋₆        alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆ alkyl),        —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆        alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆        alkyl), —OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂,        —NHSO₂(C₁₋₆ alkyl), —SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl),        —SO₂NH₂, —SO₂C₁₋₆ alkyl, —SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl,        —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃, —OSi(C₁₋₆ alkyl)₃ —C(═S)N(C₁₋₆        alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂, —C(═O)S(C₁₋₆ alkyl),        —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆ alkyl),        —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆        alkyl)₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 membered        heterocyclyl, 5-10 membered heteroaryl; or two geminal R^(gg)        substituents can be joined to form ═O or ═S; wherein X⁻ is a        counterion.

A “counterion” or “anionic counterion” is a negatively charged groupassociated with a cationic quaternary amino group in order to maintainelectronic neutrality. Exemplary counterions include halide ions (e.g.,F⁻, Cl⁻, Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HSO₄ ⁻, SO₄ ⁻² sulfonateions (e.g., methansulfonate, trifluoromethanesulfonate,p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate,naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate,ethan-1-sulfonic acid-2-sulfonate, and the like), and carboxylate ions(e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate,tartrate, glycolate, and the like).

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quarternary nitrogenatoms. Exemplary nitrogen atom substituents include, but are not limitedto, hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R—,—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂, —P(═O)(NR^(cc))₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups attached to a nitrogen atom are joinedto form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(aa) groups, and wherein R^(aa), R^(bb), R^(cc) and R^(aa) are asdefined above.

These and other exemplary substituents are described in more detail inthe Detailed Description, Examples, and claims. The invention is notintended to be limited in any manner by the above exemplary listing ofsubstituents.

Other Definitions

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.,describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences (1977) 66:1-19.

Pharmaceutically acceptable salts of the compounds of the presentinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike.

Pharmaceutically acceptable salts derived from appropriate bases includealkali metal, alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, lower alkyl sulfonate, and aryl sulfonate.

A “subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g., infant, child, adolescent) or adult subject(e.g., young adult, middle-aged adult or senior adult)) and/or anon-human animal, e.g., a mammal such as primates (e.g., cynomolgusmonkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents,cats, and/or dogs. In certain embodiments, the subject is a human. Incertain embodiments, the subject is a non-human animal. The terms“human,” “patient,” and “subject” are used interchangeably herein.

Disease, disorder, and condition are used interchangeably herein.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” contemplate an action that occurs while asubject is suffering from the specified disease, disorder or condition,which reduces the severity of the disease, disorder or condition, orretards or slows the progression of the disease, disorder or condition(“therapeutic treatment”), and also contemplates an action that occursbefore a subject begins to suffer from the specified disease, disorderor condition (“prophylactic treatment”).

In general, the “effective amount” of a compound refers to an amountsufficient to elicit the desired biological response. As will beappreciated by those of ordinary skill in this art, the effective amountof a compound of the invention may vary depending on such factors as thedesired biological endpoint, the pharmacokinetics of the compound, thedisease being treated, the mode of administration, and the age, health,and condition of the subject. An effective amount encompassestherapeutic and prophylactic treatment.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment of a disease, disorder orcondition, or to delay or minimize one or more symptoms associated withthe disease, disorder or condition. A therapeutically effective amountof a compound means an amount of therapeutic agent, alone or incombination with other therapies, which provides a therapeutic benefitin the treatment of the disease, disorder or condition. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease orcondition, or enhances the therapeutic efficacy of another therapeuticagent.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of a compound is an amount sufficient to prevent adisease, disorder or condition, or one or more symptoms associated withthe disease, disorder or condition, or prevent its recurrence. Aprophylactically effective amount of a compound means an amount of atherapeutic agent, alone or in combination with other agents, whichprovides a prophylactic benefit in the prevention of the disease,disorder or condition. The term “prophylactically effective amount” canencompass an amount that improves overall prophylaxis or enhances theprophylactic efficacy of another prophylactic agent.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

As generally described herein, the present invention providesC19-substituted neuroactive steroids designed, for example, to act asGABA modulators. In certain embodiments, such compounds are envisionedto be useful as therapeutic agents for the inducement of anesthesiaand/or sedation in a subject.

In certain embodiments, such compounds are envisioned to be useful astherapeutic agents for treating a CNS-related disorder.

Compounds

In one aspect, provided herein are compounds according to Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, carbocyclyl, or heterocyclyl; eachof R^(2a) and R^(2b) is independently hydrogen, C₁-C₆ alkyl, halo,cyano, —OR^(A), or —NR^(B)R^(C), or R^(2a) and R^(2b) together with thecarbon atom to which they are attached form a ring (e.g., a 3-7-memberedring, e.g., a 5-7-membered ring; a ring containing at least oneheteroatom, e.g., a nitrogen, oxygen, or sulfur atom); R³ is hydrogen,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, carbocyclyl, heterocyclyl,aryl, heteroaryl, —C(O)R^(A), —C(O)OR^(A), or —C(O)NR^(B)R^(C); R⁴ ishydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, carbocyclyl, or—OR^(A);

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond; wherein when the

between —CR⁶ and —CR^(5a)R^(5b)

is a double bond, then one of R^(5a) or R^(5b) is absent; and when oneof the

is a double bond, R⁶ is absent; each of R^(5a) and R^(5b) isindependently absent, hydrogen, C₁-C₆ alkyl, or halo; R⁶ is absent orhydrogen; Z is —CR^(7a)R^(7b)—, wherein each of R^(7a) and R^(7b) isindependently hydrogen or C₁-C₆ alkyl, or R^(7a) and R^(7b), togetherwith the carbon atom to which they are attached, form a ring (e.g.,carbocyclyl or heterocyclyl); R^(A) is hydrogen, C₁-C₆ alkyl,carbocyclyl, heterocyclyl, aryl, or heteroaryl; each of R^(B) and R^(C)is independently hydrogen, C₁-C₆ alkyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, or taken together with the atom to which they are attachedform a ring (e.g., a 3-7-membered ring, e.g., a 5-7-membered ring; aring containing at least one heteroatom, e.g., a nitrogen, oxygen, orsulfur atom); or R^(D) is hydrogen, C₁-C₆ alkyl, carbocyclyl,heterocyclyl, aryl, or heteroaryl.

In certain embodiments, R¹ is C₂-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,carbocyclyl, or heterocyclyl. In certain embodiments, R¹ is C₁-C₆ alkyl.In certain embodiments, R¹ is methyl.

In certain embodiments, R^(2a) or R^(2b) is hydrogen. In certainembodiments, both R^(2a) and R^(2b) are hydrogen.

In certain embodiments, R¹ is C₁-C₆ alkyl and both R^(2a) and R^(2b) arehydrogen. In certain embodiments, R¹ is methyl and R^(2a) or R^(2b) ishydrogen. In certain embodiments, R¹ is methyl and both R^(2a) andR^(2b) are hydrogen.

In certain embodiments, R³ is C₂-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,carbocyclyl, heterocyclyl, C(O)R^(A), —C(O)OR^(A), —C(O)NR^(B)R^(C), or—S(O)_(x)R^(D). In certain embodiments, R³ is C₁-C₆ alkyl, carbocyclyl,heterocyclyl, or —C(O)NR^(B)R^(C). In certain embodiments, R³ is C₁-C₆alkyl, for example, methyl, ethyl, or propyl.

In certain embodiments, R¹ is methyl and R³ is C₁-C₆ alkyl, for example,methyl, ethyl, or propyl.

In certain embodiments, R³ is heterocyclyl, for example,tetrahydropyranyl.

In certain embodiments, R¹ is methyl and R³ is heterocyclyl, forexample, tetrahydropyranyl.

In certain embodiments, R³ is C(O)NR^(B)R^(C), for example,C(O)NHCH₂CH₃.

In certain embodiments, R¹ is methyl and R³ is C(O)NR^(B)R^(C), forexample, C(O)NHCH₂CH₃.

In certain embodiments, R⁴ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,or carbocyclyl. In certain embodiments, R⁴ is —OR^(A) and R^(A) is C₁-C₆alkyl. In certain embodiments, R⁴ is hydrogen, C₁-C₆ alkyl, or —OH. Incertain embodiments, R⁴ is —OH. In certain embodiments, R⁴ is hydrogen.

In certain embodiments, the

between —CR⁶ and —CR^(5a)R^(5b) is a single bond, and R^(5a) or R^(5b)is hydrogen.

In certain embodiments, R¹ is methyl, the

between —CR⁶ and —CR^(5a)R^(5b) is a single bond, and R^(5a) or R^(5b)is hydrogen.

In certain embodiments, the

between —CR⁶ and —CR^(5a)R^(5b) is a single bond, and both R^(5a) andR^(5b) are hydrogen.

In certain embodiments, R¹ is methyl, the

between —CR⁶ and —CR^(5a)R^(5b) is a single bond, and both R^(5a) andR^(5b) are hydrogen.

In certain embodiments, both R^(2a) and R^(2b) are hydrogen, the

between —CR⁶ and —CR^(5a)R^(5b) is a single bond, and R^(5a) or R^(5b)is hydrogen. In certain embodiments, both R^(2a) and R^(2b) arehydrogen, the

between —CR⁶ and —CR^(5a)R^(5b) is a single bond, and both R^(5a) andR^(5b) are hydrogen.

In certain embodiments, R⁴ is C₁-C₆ alkyl or —CR^(A), the

between —CR⁶ and —CR^(5a)R^(5b) is a single bond, and R^(5a) or R^(5b)is hydrogen. In certain embodiments, R⁴ is C₁-C₆ alkyl or —OR^(A), the

between —CR⁶ and —CR^(5a)R^(5b) is a single bond, and both R^(5a) andR^(5b) are hydrogen.

In certain embodiments, the

between —CR⁶ and —CR^(5a)R^(5b) is a double bond, one of R^(5a) orR^(5b) is hydrogen, and the other of R^(5a) or R^(5b) is absent.

In certain embodiments, Z is R^(7a) is hydrogen. In certain embodiments,Z is R^(7b) is hydrogen. In certain embodiments, Z is R^(7a) is C₁-C₆alkyl. In certain embodiments, Z is R^(7b) is C₁-C₆ alkyl. In certainembodiments, Z is R^(7a) is hydrogen and R^(7b) is C₁-C₆ alkyl. Incertain embodiments, Z is R^(7b) is —CH₃.

In certain embodiments, Z is —CH₂—.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (Ia):

or a pharmaceutically acceptable salt thereof, wherein R¹ is C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, carbocyclyl, or heterocyclyl; eachof R^(2a) and R^(2b) is independently hydrogen, C₁-C₆ alkyl, halo,cyano, —OR^(A), or —NR^(B)R^(C), or R^(2a) and R^(2b) together with thecarbon atom to which they are attached form a ring (e.g., a 3-7-memberedring, e.g., a 5-7-membered ring; a ring containing at least oneheteroatom, e.g., a nitrogen, oxygen, or sulfur atom); R³ is hydrogen,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, carbocyclyl, heterocyclyl,aryl, heteroaryl, —C(O)R^(A), —C(O)OR^(A), or —C(O)NR^(B)R^(C); R⁴ ishydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, carbocyclyl, orOR^(A); each of R^(5a) and R^(5b) is independently absent, hydrogen,C₁-C₆ alkyl, or halo; Z is —CR^(7a)R^(7b)—, wherein each of R^(7a) andR^(7b) is independently hydrogen or C₁-C₆ alkyl, or R^(7a) and R^(7b),together with the carbon atom to which they are attached, form a ring(e.g., carbocyclyl or heterocyclyl); R^(A) is hydrogen, C₁-C₆ alkyl,carbocyclyl, heterocyclyl, aryl, or heteroaryl; each of R^(B) and R^(C)is independently hydrogen, C₁-C₆ alkyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, or taken together with the atom to which they are attachedform a ring (e.g., a 3-7-membered ring, e.g., a 5-7-membered ring; aring containing at least one heteroatom, e.g., a nitrogen, oxygen, orsulfur atom); or R^(D) is hydrogen, C₁-C₆ alkyl, carbocyclyl,heterocyclyl, aryl, or heteroaryl.

In certain embodiments, R is C₂-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,carbocyclyl, or heterocyclyl. In certain embodiments, R¹ is C₁-C₆ alkyl.In certain embodiments, R¹ is methyl.

In certain embodiments, R^(2a) or R^(2b) is hydrogen. In certainembodiments, both R^(2a) and R^(2b) are hydrogen.

In certain embodiments, R¹ is C₁-C₆ alkyl and both R^(2a) and R^(2b) arehydrogen. In certain embodiments, R¹ is methyl and R^(2a) or R^(2b) ishydrogen. In certain embodiments, R¹ is methyl and both R^(2a) andR^(2b) are hydrogen.

In certain embodiments, R³ is C₂-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,carbocyclyl, heterocyclyl, —C(O)R^(A), —C(O)OR^(A), —C(O)NR^(B)R^(C), or—S(O)_(x)R^(D). In certain embodiments, R³ is C₁-C₆ alkyl, carbocyclyl,heterocyclyl, or —C(O)NR^(B)R^(C). In certain embodiments, R³ is C₁-C₆alkyl, for example, methyl, ethyl, or propyl.

In certain embodiments, R¹ is methyl and R is C₁-C₆ alkyl, for example,methyl, ethyl, or propyl.

In certain embodiments, R⁴ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,or carbocyclyl. In certain embodiments, R⁴ is hydrogen, C₁-C₆ alkyl, or—OH. In certain embodiments, R⁴ is hydrogen.

In certain embodiments, R^(5a) or R^(5b) is hydrogen.

In certain embodiments, R¹ is methyl and R^(5a) or R^(5b) is hydrogen.

In certain embodiments, both R^(5a) and R^(5b) are hydrogen.

In certain embodiments, R¹ is methyl and both R^(5a) and R^(5b) arehydrogen.

In certain embodiments, both R^(2a) and R^(2b) are hydrogen and R^(5a)or R^(5b) is hydrogen. In certain embodiments, both R^(2a) and R^(2b)are hydrogen and both R^(5a) and R^(5b) are hydrogen.

In certain embodiments, R⁴ is C₁-C₆ alkyl and R^(5a) or R^(5b) ishydrogen. In certain embodiments, R⁴ is C₁-C₆ alkyl and both R^(5a) andR^(5b) are hydrogen.

In certain embodiments, the compound of Formula (Ia) is selected from:

In certain embodiments, the compound of Formula (I) is a compound ofFormula (Ib):

or a pharmaceutically acceptable salt thereof, wherein R¹ is C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, carbocyclyl, or heterocyclyl; eachof R^(2a) and R^(2b) is independently hydrogen, C₁-C₆ alkyl, halo,cyano, —OR^(A), or —NR^(B)R^(C), or R^(2a) and R^(2b) together with thecarbon atom to which they are attached form a ring (e.g., a 3-7-memberedring, e.g., a 5-7-membered ring; a ring containing at least oneheteroatom, e.g., a nitrogen, oxygen, or sulfur atom); R³ is hydrogen,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, carbocyclyl, heterocyclyl,aryl, heteroaryl, —C(O)R^(A), —C(O)OR^(A), or —C(O)NR^(B)R^(C); R⁴ ishydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, carbocyclyl, orOR^(A); each of R^(5a) and R^(5b) is independently absent, hydrogen,C₁-C₆ alkyl, or halo; Z is —CR^(7a)R^(7b)—, wherein each of R^(7a) andR^(7b) is independently hydrogen or C₁-C₆ alkyl, or R^(7a) and R^(7b),together with the carbon atom to which they are attached, form a ring(e.g., carbocyclyl or heterocyclyl); R^(A) is hydrogen, C₁-C₆ alkyl,carbocyclyl, heterocyclyl, aryl, or heteroaryl; each of R^(B) and R^(C)is independently hydrogen, C₁-C₆ alkyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, or taken together with the atom to which they are attachedform a ring (e.g., a 3-7-membered ring, e.g., a 5-7-membered ring; aring containing at least one heteroatom, e.g., a nitrogen, oxygen, orsulfur atom); or R^(D) is hydrogen, C₁-C₆ alkyl, carbocyclyl,heterocyclyl, aryl, or heteroaryl.

In certain embodiments, R¹ is C₂-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,carbocyclyl, or heterocyclyl. In certain embodiments, R¹ is C₁-C₆ alkyl.In certain embodiments, R¹ is methyl.

In certain embodiments, R^(2a) or R^(2b) is hydrogen. In certainembodiments, both R^(2a) and R^(2b) are hydrogen.

In certain embodiments, R¹ is C₁-C₆ alkyl and both R^(2a) and R^(2b) arehydrogen. In certain embodiments, R¹ is methyl and R^(2a) or R^(2b) ishydrogen. In certain embodiments, R¹ is methyl and both R^(2a) andR^(2b) are hydrogen.

In certain embodiments, R³ is C₂-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,carbocyclyl, heterocyclyl, —C(O)R^(A), —C(O)OR^(A), —C(O)NR^(B)R^(C), or—S(O)_(x)R^(D). In certain embodiments, R³ is C₁-C₆ alkyl, for example,methyl, ethyl, or propyl.

In certain embodiments, R¹ is methyl and R³ is C₁-C₆ alkyl, for example,methyl, ethyl, or propyl.

In certain embodiments, R³ is heterocyclyl, for example,tetrahydropyranyl.

In certain embodiments, R¹ is methyl and R³ is heterocyclyl, forexample, tetrahydropyranyl.

In certain embodiments, R³ is C(O)NR^(B)R^(C), for example,C(O)NHCH₂CH₃.

In certain embodiments, R¹ is methyl and R³ is C(O)NR^(B)R^(C), forexample, C(O)NHCH₂CH₃.

In certain embodiments, R⁴ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,or carbocyclyl. In certain embodiments, R⁴ is hydrogen, C₁-C₆ alkyl, orhydroxyl. In certain embodiments, R⁴ is —OH. In certain embodiments, R⁴is hydrogen.

In certain embodiments, R^(5a) or R^(5b) is hydrogen.

In certain embodiments, R¹ is methyl and R^(5a) or R^(5b) is hydrogen.

In certain embodiments, both R^(5a) and R^(5b) are hydrogen.

In certain embodiments, R¹ is methyl and both R^(5a) and R^(5b) arehydrogen.

In certain embodiments, both R^(2a) and R^(2b) are hydrogen and R^(5a)or R^(5b) is hydrogen. In certain embodiments, both R^(2a) and R^(2b)are hydrogen and both R^(5a) and R^(5b) are hydrogen.

In certain embodiments, R⁴ is C₁-C₆ alkyl and R^(5a) or R^(5b) ishydrogen. In certain embodiments, R⁴ is C₁-C₆ alkyl and both R^(5a) andR^(5b) are hydrogen.

In certain embodiments, the compound of Formula (Ib) is selected from:

A pharmaceutical composition comprising a compound as described herein,e.g., a compound of Formula (I), or pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable excipient.

A method for treating a CNS-related disorder in a subject in needthereof, comprising administering to the subject an effective amount ofa compound as described herein, e.g., a compound of Formula (I), orpharmaceutically acceptable salt thereof. In certain embodiments, theCNS-related disorder is a sleep disorder, a mood disorder, aschizophrenia spectrum disorder, a convulsive disorder, a disorder ofmemory and/or cognition, a movement disorder, a personality disorder, asleep disorder, autism spectrum disorder, pain, seizure, statusepilepticus, depression (e.g., postnatal depression, postpartumdepression), traumatic brain injury, a vascular disease, a substanceabuse disorder and/or withdrawal syndrome, or tinnitus. In certainembodiments, the compound is administered orally, subcutaneously,intravenously, or intramuscularly. In certain embodiments, the compoundis administered chronically.

A method for inducing anesthesia or sedation, comprising administeringto the subject an effective amount of a compound as described herein,e.g., a compound of Formula (I), or pharmaceutically acceptable saltthereof.

Pharmaceutical Compositions

In another aspect, the invention provides a pharmaceutical compositioncomprising a compound of the present invention (also referred to as the“active ingredient”) and a pharmaceutically acceptable excipient. Incertain embodiments, the pharmaceutical composition comprises aneffective amount of the active ingredient. In certain embodiments, thepharmaceutical composition comprises a therapeutically effective amountof the active ingredient. In certain embodiments, the pharmaceuticalcomposition comprises a prophylactically effective amount of the activeingredient.

The pharmaceutical compositions provided herein can be administered by avariety of routes including, but not limited to, oral (enteral)administration, parenteral (by injection) administration, rectaladministration, transdermal administration, intradermal administration,intrathecal administration, subcutaneous (SC) administration,intravenous (IV) administration, intramuscular (IM) administration, andintranasal administration.

Generally, the compounds provided herein are administered in aneffective amount. The amount of the compound actually administered willtypically be determined by a physician, in the light of the relevantcircumstances, including the condition to be treated, the chosen routeof administration, the actual compound administered, the age, weight,and response of the individual patient, the severity of the patient'ssymptoms, and the like.

When used to prevent the onset of a CNS-disorder, the compounds providedherein will be administered to a subject at risk for developing thecondition, typically on the advice and under the supervision of aphysician, at the dosage levels described above. Subjects at risk fordeveloping a particular condition generally include those that have afamily history of the condition, or those who have been identified bygenetic testing or screening to be particularly susceptible todeveloping the condition.

The pharmaceutical compositions provided herein can also be administeredchronically (“chronic administration”). Chronic administration refers toadministration of a compound or pharmaceutical composition thereof overan extended period of time, e.g., for example, over 3 months, 6 months,1 year, 2 years, 3 years, 5 years, etc., or may be continuedindefinitely, for example, for the rest of the subject's life. Incertain embodiments, the chronic administration is intended to provide aconstant level of the compound in the blood, e.g., within thetherapeutic window over the extended period of time.

The pharmaceutical compostions of the present invention may be furtherdelivered using a variety of dosing methods. For example, in certainembodiments, the pharmaceutical composition may be given as a bolus,e.g., in order to raise the concentration of the compound in the bloodto an effective level. The placement of the bolus dose depends on thesystemic levels of the active ingredient desired throughout the body,e.g., an intramuscular or subcutaneous bolus dose allows a slow releaseof the active ingredient, while a bolus delivered directly to the veins(e.g., through an IV drip) allows a much faster delivery which quicklyraises the concentration of the active ingredient in the blood to aneffective level. In other embodiments, the pharmaceutical compositionmay be administered as a continuous infusion, e.g., by IV drip, toprovide maintenance of a steady-state concentration of the activeingredient in the subject's body.

Furthermore, in still yet other embodiments, the pharmaceuticalcomposition may be administered as first as a bolus dose, followed bycontinuous infusion.

The compositions for oral administration can take the form of bulkliquid solutions or suspensions, or bulk powders. More commonly,however, the compositions are presented in unit dosage forms tofacilitate accurate dosing. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient. Typical unitdosage forms include prefilled, premeasured ampules or syringes of theliquid compositions or pills, tablets, capsules or the like in the caseof solid compositions. In such compositions, the compound is usually aminor component (from about 0.1 to about 50% by weight or preferablyfrom about 1 to about 40% by weight) with the remainder being variousvehicles or excipients and processing aids helpful for forming thedesired dosing form.

With oral dosing, one to five and especially two to four and typicallythree oral doses per day are representative regimens. Using these dosingpatterns, each dose provides from about 0.01 to about 20 mg/kg of thecompound provided herein, with preferred doses each providing from about0.1 to about 10 mg/kg, and especially about 1 to about 5 mg/kg.

Transdermal doses are generally selected to provide similar or lowerblood levels than are achieved using injection doses, generally in anamount ranging from about 0.01 to about 20% by weight, preferably fromabout 0.1 to about 20% by weight, preferably from about 0.1 to about 10%by weight, and more preferably from about 0.5 to about 15% by weight.

Injection dose levels range from about 0.1 mg/kg/hour to at least 10mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kgor more may also be administered to achieve adequate steady statelevels. The maximum total dose is not expected to exceed about 2 g/dayfor a 40 to 80 kg human patient.

Liquid forms suitable for oral administration may include a suitableaqueous or nonaqueous vehicle with buffers, suspending and dispensingagents, colorants, flavors and the like. Solid forms may include, forexample, any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable excipients knownin the art. As before, the active compound in such compositions istypically a minor component, often being from about 0.05 to 10% byweight with the remainder being the injectable excipient and the like.

Transdermal compositions are typically formulated as a topical ointmentor cream containing the active ingredient(s). When formulated as aointment, the active ingredients will typically be combined with eithera paraffinic or a water-miscible ointment base. Alternatively, theactive ingredients may be formulated in a cream with, for example anoil-in-water cream base. Such transdermal formulations are well-known inthe art and generally include additional ingredients to enhance thedermal penetration of stability of the active ingredients orFormulation. All such known transdermal formulations and ingredients areincluded within the scope provided herein.

The compounds provided herein can also be administered by a transdermaldevice. Accordingly, transdermal administration can be accomplishedusing a patch either of the reservoir or porous membrane type, or of asolid matrix variety.

The above-described components for orally administrable, injectable ortopically administrable compositions are merely representative. Othermaterials as well as processing techniques and the like are set forth inPart 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, MackPublishing Company, Easton, Pennsylvania, which is incorporated hereinby reference.

The compounds of the present invention can also be administered insustained release forms or from sustained release drug delivery systems.A description of representative sustained release materials can be foundin Remington's Pharmaceutical Sciences.

The present invention also relates to the pharmaceutically acceptableformulations of a compound of the present invention. In one embodiment,the formulation comprises water. In another embodiment, the formulationcomprises a cyclodextrin derivative. The most common cyclodextrins areα-, β- and γ-cyclodextrins consisting of 6, 7 and 8 α-1,4-linked glucoseunits, respectively, optionally comprising one or more substituents onthe linked sugar moieties, which include, but are not limited to,methylated, hydroxyalkylated, acylated, and sulfoalkylethersubstitution. In certain embodiments, the cyclodextrin is a sulfoalkylether p-cyclodextrin, e.g., for example, sulfobutyl etherp-cyclodextrin, also known as Captisol®. See, e.g., U.S. Pat. No.5,376,645. In certain embodiments, the formulation compriseshexapropyl-p-cyclodextrin (e.g., 10-50% in water).

The present invention also relates to the pharmaceutically acceptableacid addition salt of a compound of the present invention. The acidwhich may be used to prepare the pharmaceutically acceptable salt isthat which forms a non-toxic acid addition salt, i.e., a salt containingpharmacologically acceptable anions such as the hydrochloride,hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate,acetate, lactate, citrate, tartrate, succinate, maleate, fumarate,benzoate, para-toluenesulfonate, and the like.

The following formulation examples illustrate representativepharmaceutical compositions that may be prepared in accordance with thisinvention. The present invention, however, is not limited to thefollowing pharmaceutical compositions.

Exemplary Formulation 1—Tablets: A compound of the present invention maybe admixed as a dry powder with a dry gelatin binder in an approximate1:2 weight ratio. A minor amount of magnesium stearate is added as alubricant. The mixture is formed into 240-270 mg tablets (80-90 mg ofactive compound per tablet) in a tablet press.

Exemplary Formulation 2—Capsules: A compound of the present inventionmay be admixed as a dry powder with a starch diluent in an approximate1:1 weight ratio. The mixture is filled into 250 mg capsules (125 mg ofactive compound per capsule).

Exemplary Formulation 3—Liquid: A compound of the present invention (125mg) may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and theresultant mixture may be blended, passed through a No. 10 mesh U.S.sieve, and then mixed with a previously made solution ofmicrocrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50mg) in water. Sodium benzoate (10 mg), flavor, and color are dilutedwith water and added with stirring. Sufficient water may then be addedto produce a total volume of 5 mL.

Exemplary Formulation 4—Tablets: A compound of the present invention maybe admixed as a dry powder with a dry gelatin binder in an approximate1:2 weight ratio. A minor amount of magnesium stearate is added as alubricant. The mixture is formed into 450-900 mg tablets (150-300 mg ofactive compound) in a tablet press.

Exemplary Formulation 5—Injection: A compound of the present inventionmay be dissolved or suspended in a buffered sterile saline injectableaqueous medium to a concentration of approximately 5 mg/mL.

Exemplary Formulation 6—Tablets: A compound of the present invention maybe admixed as a dry powder with a dry gelatin binder in an approximate1:2 weight ratio. A minor amount of magnesium stearate is added as alubricant. The mixture is formed into 90-150 mg tablets (30-50 mg ofactive compound per tablet) in a tablet press.

Exemplary Formulation 7—Tablets: A compound of the present invention maybe admixed as a dry powder with a dry gelatin binder in an approximate1:2 weight ratio. A minor amount of magnesium stearate is added as alubricant. The mixture is formed into 30-90 mg tablets (10-30 mg ofactive compound per tablet) in a tablet press.

Exemplary Formulation 8—Tablets: A compound of the present invention maybe admixed as a dry powder with a dry gelatin binder in an approximate1:2 weight ratio. A minor amount of magnesium stearate is added as alubricant. The mixture is formed into 0.3-30 mg tablets (0.1-10 mg ofactive compound per tablet) in a tablet press.

Exemplary Formulation 9—Tablets: A compound of the present invention maybe admixed as a dry powder with a dry gelatin binder in an approximate1:2 weight ratio. A minor amount of magnesium stearate is added as alubricant. The mixture is formed into 150-240 mg tablets (50-80 mg ofactive compound per tablet) in a tablet press.

Exemplary Formulation 10—Tablets: A compound of the present inventionmay be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 270-450 mg tablets(90-150 mg of active compound per tablet) in a tablet press.

Methods of Use and Treatment

As generally described herein, the present invention is directed toC19-substituted neuroactive steroids designed, for example, to act asGABA modulators. In certain embodiments, such compounds are envisionedto be useful as therapeutic agents for the inducement of anesthesiaand/or sedation in a subject. In some embodiments, such compounds areenvisioned to be useful as therapeutic agents for treating a CNS-relateddisorder (e.g., sleep disorder, a mood disorder, a schizophreniaspectrum disorder, a convulsive disorder, a disorder of memory and/orcognition, a movement disorder, a personality disorder, autism spectrumdisorder, pain, traumatic brain injury, a vascular disease, a substanceabuse disorder and/or withdrawal syndrome, or tinnitus) in a subject inneed (e.g., a subject with Rett syndrome, Fragile X syndrome, orAngelman syndrome).

Thus, in one aspect, the present invention provides a method of inducingsedation and/or anesthesia in a subject, comprising administering to thesubject an effective amount of a compound of the present invention or acomposition thereof. In certain embodiments, the compound isadministered by intravenous administration.

Earlier studies (see, e.g., Gee et al., European Journal ofPharmacology, 136:419-423 (1987)) demonstrated that certain3α-hydroxylated steroids are orders of magnitude more potent asmodulators of the GABA receptor complex (GRC) than others had reported(see, e.g., Majewska et al., Science 232:1004-1007 (1986); Harrison etal., J Pharmacol. Exp. Ther. 241:346-353 (1987)). Majewska et al. andHarrison et al. taught that 3α-hydroxylated-5-reduced steroids are onlycapable of much lower levels of effectiveness. In vitro and in vivoexperimental data have now demonstrated that the high potency of thesesteroids allows them to be therapeutically useful in the modulation ofbrain excitability via the GRC (see, e.g., Gee et al., European Journalof Pharmacology, 136:419-423 (1987); Wieland et al., Psychopharmacology118(1):65-71 (1995)).

Various synthetic steroids have also been prepared as neuroactivesteroids. See, for example, U.S. Pat. No. 5,232,917, which disclosesneuroactive steroid compounds useful in treating stress, anxiety,insomnia, seizure disorders, and mood disorders, that are amenable toGRC-active agents, such as depression, in a therapeutically beneficialmanner. Furthermore, it has been previously demonstrated that thesesteroids interact at a unique site on the GRC which is distinct fromother known sites of interaction (e.g., barbiturates, benzodiazepines,and GABA) where therapeutically beneficial effects on stress, anxiety,sleep, mood disorders and seizure disorders have been previouslyelicited (see, e.g., Gee, K. W. and Yamamura, H. I., “Benzodiazepinesand Barbiturates: Drugs for the Treatment of Anxiety, Insomnia andSeizure Disorders,” in Central Nervous System Disorders, Horvell, ed.,Marcel-Dekker, New York (1985), pp. 123-147; Lloyd, K. G. and Morselli,P. L., “Psychopharmacology of GABAergic Drugs,” in Psychopharmacology:The Third Generation of Progress, H. Y. Meltzer, ed., Raven Press, N.Y.(1987), pp. 183-195; and Gee et al., European Journal of Pharmacology,136:419-423 (1987). These compounds are desirable for their duration,potency, and oral activity (along with other forms of administration).

Compounds of the present invention, as described herein, are generallydesigned to modulate GABA function, and therefore to act as neuroactivesteroids for the treatment and prevention of CNS-related conditions in asubject. Modulation, as used herein, refers to the inhibition orpotentiation of GABA receptor function. Accordingly, the compounds andpharmaceutical compositions provided herein find use as therapeutics forpreventing and/or treating CNS conditions in mammals including humansand non-human mammals. Thus, and as stated earlier, the presentinvention includes within its scope, and extends to, the recited methodsof treatment, as well as to the compounds for such methods, and to theuse of such compounds for the preparation of medicaments useful for suchmethods.

Exemplary CNS conditions related to GABA-modulation include, but are notlimited to, sleep disorders [e.g., insomnia], mood disorders [e.g.,depression, dysthymic disorder (e.g., mild depression), bipolar disorder(e.g., I and/or II), anxiety disorders (e.g., generalized anxietydisorder (GAD), social anxiety disorder), stress, post-traumatic stressdisorder (PTSD), compulsive disorders (e.g., obsessive compulsivedisorder (OCD))], schizophrenia spectrum disorders [e.g., schizophrenia,schizoaffective disorder], convulsive disorders [e.g., epilepsy (e.g.,status epilepticus (SE)), seizures], disorders of memory and/orcognition [e.g., attention disorders (e.g., attention deficithyperactivity disorder (ADHD)), dementia (e.g., Alzheimer's typedementia, Lewis body type dementia, vascular type dementia], movementdisorders [e.g., Huntington's disease, Parkinson's disease], personalitydisorders [e.g., anti-social personality disorder, obsessive compulsivepersonality disorder], autism spectrum disorders (ASD) [e.g., autism,monogenetic causes of autism such as synaptophathy's, e.g., Rettsyndrome, Fragile X syndrome, Angelman syndrome], pain [e.g.,neuropathic pain, injury related pain syndromes, acute pain, chronicpain], traumatic brain injury (TBI), vascular diseases [e.g., stroke,ischemia, vascular malformations], substance abuse disorders and/orwithdrawal syndromes [e.g., addition to opiates, cocaine, and/oralcohol], and tinnitus.

In yet another aspect, provided is a combination of a compound of thepresent invention and another pharmacologically active agent. Thecompounds provided herein can be administered as the sole active agentor they can be administered in combination with other agents.Administration in combination can proceed by any technique apparent tothose of skill in the art including, for example, separate, sequential,concurrent and alternating administration.

In another aspect, provided is a method of treating or preventing brainexcitability in a subject susceptible to or afflicted with a conditionassociated with brain excitability, comprising administering to thesubject an effective amount of a compound of the present invention tothe subject.

In yet another aspect, provided is a method of treating or preventingstress or anxiety in a subject, comprising administering to the subjectin need of such treatment an effective amount of a compound of thepresent invention, or a composition thereof.

In yet another aspect, provided is a method of alleviating or preventingseizure activity in a subject, comprising administering to the subjectin need of such treatment an effective amount of a compound of thepresent invention.

In yet another aspect, provided is a method of alleviating or preventinginsomnia in a subject, comprising administering to the subject in needof such treatment an effective amount of a compound of the presentinvention, or a composition thereof.

In yet another aspect, provided is a method of inducing sleep andmaintaining substantially the level of REM sleep that is found in normalsleep, wherein substantial rebound insomnia is not induced, comprisingadministering an effective amount of a compound of the presentinvention.

In yet another aspect, provided is a method of alleviating or preventingPMS or PND in a subject, comprising administering to the subject in needof such treatment an effective amount of a compound of the presentinvention.

In yet another aspect, provided is a method of treating or preventingmood disorders in a subject, comprising administering to the subject inneed of such treatment an effective amount of a compound of the presentinvention. In certain embodiments the mood disorder is depression.

In yet another aspect, provided is a method of inducing anesthesia in asubject, comprising administering to the subject an effective amount ofa compound of the present invention.

In yet another aspect, provided is a method of cognition enhancement ortreating memory disorder by administering to the subject atherapeutically effective amount of a compound of the present invention.In certain embodiments, the disorder is Alzheimer's disease. In certainembodiments, the disorder is Rett syndrome.

In yet another aspect, provided is a method of treating attentiondisorders by administering to the subject a therapeutically effectiveamount of a compound of the present invention. In certain embodiments,the attention disorder is ADHD.

In certain embodiments, the compound is administered to the subjectchronically. In certain embodiments, the compound is administered to thesubject orally, subcutaneously, intramuscularly, or intravenously.

Neurodegenerative Diseases and Disorders

The compounds described herein can be used in a method described herein,for example in the treatment of a disorder described herein such as aneurodegenerative disease.

The term “neurodegenerative disease” includes diseases and disordersthat are associated with the progressive loss of structure or functionof neurons, or death of neurons. Neurodegenerative diseases anddisorders include, but are not limited to, Alzheimer's disease(including the associated symptoms of mild, moderate, or severecognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic andischemic injuries; ataxia and convulsion (including for the treatmentand prevention and prevention of seizures that are caused byschizoaffective disorder or by drugs used to treat schizophrenia);benign forgetfulness; brain edema; cerebellar ataxia including McLeodneuroacanthocytosis syndrome (MLS); closed head injury; coma; contusiveinjuries (e.g., spinal cord injury and head injury); dementias includingmulti-infarct dementia and senile dementia; disturbances ofconsciousness; Down syndrome; drug-induced or medication-inducedParkinsonism (such as neuroleptic-induced acute akathisia, acutedystonia, Parkinsonism, or tardive dyskinesia, neuroleptic malignantsyndrome, or medication-induced postural tremor); epilepsy; fragile Xsyndrome; Gilles de la Tourette's syndrome; head trauma; hearingimpairment and loss; Huntington's disease; Lennox syndrome;levodopa-induced dyskinesia; mental retardation; movement disordersincluding akinesias and akinetic (rigid) syndromes (including basalganglia calcification, corticobasal degeneration, multiple systematrophy, Parkinsonism-ALS dementia complex, Parkinson's disease,postencephalitic parkinsonism, and progressively supranuclear palsy);muscular spasms and disorders associated with muscular spasticity orweakness including chorea (such as benign hereditary chorea,drug-induced chorea, hemiballism, Huntington's disease,neuroacanthocytosis, Sydenham's chorea, and symptomatic chorea),dyskinesia (including tics such as complex tics, simple tics, andsymptomatic tics), myoclonus (including generalized myoclonus and focalcyloclonus), tremor (such as rest tremor, postural tremor, and intentiontremor) and dystonia (including axial dystonia, dystonic writer's cramp,hemiplegic dystonia, paroxysmal dystonia, and focal dystonia such asblepharospasm, oromandibular dystonia, and spasmodic dysphonia andtorticollis); neuronal damage including ocular damage, retinopathy ormacular degeneration of the eye; neurotoxic injury which followscerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebralischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia,perinatal asphyxia and cardiac arrest; Parkinson's disease; seizure;status epilecticus; stroke; tinnitus; tubular sclerosis, and viralinfection induced neurodegeneration (e.g., caused by acquiredimmunodeficiency syndrome (AIDS) and encephalopathies).Neurodegenerative diseases also include, but are not limited to,neurotoxic injury which follows cerebral stroke, thromboembolic stroke,hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia,amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest. Methodsof treating or preventing a neurodegenerative disease also includetreating or preventing loss of neuronal function characteristic ofneurodegenerative disorder.

Mood Disorders

The compounds described herein can be used in a method described herein,for example in the treatment of a disorder described herein such as amood disorder.

Clinical depression is also known as major depression, major depressivedisorder (MDD), severe depression, unipolar depression, unipolardisorder, and recurrent depression, and refers to a mental disordercharacterized by pervasive and persistent low mood that is accompaniedby low self-esteem and loss of interest or pleasure in normallyenjoyable activities. Some people with clinical depression have troublesleeping, lose weight, and generally feel agitated and irritable.Clinical depression affects how an individual feels, thinks, and behavesand may lead to a variety of emotional and physical problems.Individuals with clinical depression may have trouble doing day-to-dayactivities and make an individual feel as if life is not worth living.

Postnatal depression (PND) is also referred to as postpartum depression(PPD), and refers to a type of clinical depression that affects womenafter childbirth. Symptoms can include sadness, fatigue, changes insleeping and eating habits, reduced sexual desire, crying episodes,anxiety, and irritability. In some embodiments, the PND is atreatment-resistant depression (e.g., a treatment-resistant depressionas described herein). In some embodiments, the PND is refractorydepression (e.g., a refractory depression as described herein).

Atypical depression (AD) is characterized by mood reactivity (e.g.,paradoxical anhedonia) and positivity, significant weight gain orincreased appetite. Patients suffering from AD also may have excessivesleep or somnolence (hypersomnia), a sensation of limb heaviness, andsignificant social impairment as a consequence of hypersensitivity toperceived interpersonal rejection.

Melancholic depression is characterized by loss of pleasure (anhedonia)in most or all activities, failures to react to pleasurable stimuli,depressed mood more pronounced than that of grief or loss, excessiveweight loss, or excessive guilt.

Psychotic major depression (PMD) or psychotic depression refers to amajor depressive episode, in particular of melancholic nature, where theindividual experiences psychotic symptoms such as delusions andhallucinations.

Catatonic depression refers to major depression involving disturbancesof motor behavior and other symptoms. An individual may become mute andstuporose, and either is immobile or exhibits purposeless or bizarremovements.

Seasonal affective disorder (SAD) refers to a type of seasonaldepression wherein an individual has seasonal patterns of depressiveepisodes coming on in the fall or winter.

Dysthymia refers to a condition related to unipolar depression, wherethe same physical and cognitive problems are evident. They are not assevere and tend to last longer (e.g., at least 2 years).

Double depression refers to fairly depressed mood (dysthymia) that lastsfor at least 2 years and is punctuated by periods of major depression.

Depressive Personality Disorder (DPD) refers to a personality disorderwith depressive features.

Recurrent Brief Depression (RBD) refers to a condition in whichindividuals have depressive episodes about once per month, each episodelasting 2 weeks or less and typically less than 2-3 days.

Minor depressive disorder or minor depression refers to a depression inwhich at least 2 symptoms are present for 2 weeks.

Bipolar disorder or manic depressive disorder causes extreme mood swingsthat include emotional highs (mania or hypomania) and lows (depression).During periods of mania the individual may feel or act abnormally happy,energetic, or irritable. They often make poorly thought out decisionswith little regard to the consequences. The need for sleep is usuallyreduced. During periods of depression there may be crying, poor eyecontact with others, and a negative outlook on life. The risk of suicideamong those with the disorder is high at greater than 6% over 20 years,while self harm occurs in 30-40%. Other mental health issues such asanxiety disorder and substance use disorder are commonly associated withbipolar disorder.

Depression caused by chronic medical conditions refers to depressioncaused by chronic medical conditions such as cancer or chronic pain,chemotherapy, chronic stress.

Treatment-resistant depression refers to a condition where theindividuals have been treated for depression, but the symptoms do notimprove. For example, antidepressants or psychological counseling(psychotherapy) do not ease depression symptoms for individuals withtreatment-resistant depression. In some cases, individuals withtreatment-resistant depression improve symptoms, but come back.Refractory depression occurs in patients suffering from depression whoare resistant to standard pharmacological treatments, includingtricyclic antidepressants, MAOIs, SSRIs, and double and triple uptakeinhibitors and/or anxiolytic drugs, as well as non-pharmacologicaltreatments (e.g., psychotherapy, electroconvulsive therapy, vagus nervestimulation and/or transcranial magnetic stimulation).

Suicidality, suicidal ideation, suicidal behavior refers to the tendencyof an individual to commit suicide. Suicidal ideation concerns thoughtsabout or an unusual preoccupation with suicide. The range of suicidalideation varies greatly, from e.g., fleeting thoughts to extensivethoughts, detailed planning, role playing, incomplete attempts. Symptomsinclude talking about suicide, getting the means to commit suicide,withdrawing from social contact, being preoccupied with death, feelingtrapped or hopeless about a situation, increasing use of alcohol ordrugs, doing risky or self-destructive things, saying goodbye to peopleas if they won't be seen again.

Premenstrual dysphoric disorder (PMDD) refers to a severe, at timesdisabling extension of premenstrual syndrome (PMS). PMDD causes extrememodd shifts with symptoms that typically begin seven to ten days beforea female's period starts and continues for the first few days of afemale's period. Symptoms include sadness or hopelessness, anxiety ortension, extreme moodiness, and marked irritability or anger.

Symptoms of depression include persistent anxious or sad feelings,feelings of helplessness, hopelessness, pessimism, worthlessness, lowenergy, restlessness, irritability, fatigue, loss of interest inpleasurable activities or hobbies, absence of positive thoughts orplans, excessive sleeping, overeating, appetite loss, insomnia,self-harm, thoughts of suicide, and suicide attempts. The presence,severity, frequency, and duration of symptoms may vary on a case to casebasis. Symptoms of depression, and relief of the same, may beascertained by a physician or psychologist (e.g., by a mental stateexamination).

Anxiety Disorders

The compounds described herein can be used in a method described herein,for example in the treatment of a disorder described herein such as ananxiety disorder.

Anxiety disorder is a blanket term covering several different forms ofabnormal and pathological fear and anxiety. Current psychiatricdiagnostic criteria recognize a wide variety of anxiety disorders.

Generalized anxiety disorder is a common chronic disorder characterizedby long-lasting anxiety that is not focused on any one object orsituation. Those suffering from generalized anxiety experiencenon-specific persistent fear and worry and become overly concerned witheveryday matters. Generalized anxiety disorder is the most commonanxiety disorder to affect older adults.

In panic disorder, a person suffers from brief attacks of intense terrorand apprehension, often marked by trembling, shaking, confusion,dizziness, nausea, difficulty breathing. These panic attacks, defined bythe APA as fear or discomfort that abruptly arises and peaks in lessthan ten minutes, can last for several hours and can be triggered bystress, fear, or even exercise; although the specific cause is notalways apparent. In addition to recurrent unexpected panic attacks, adiagnosis of panic disorder also requires that said attacks have chronicconsequences: either worry over the attacks' potential implications,persistent fear of future attacks, or significant changes in behaviorrelated to the attacks. Accordingly, those suffering from panic disorderexperience symptoms even outside of specific panic episodes. Often,normal changes in heartbeat are noticed by a panic sufferer, leadingthem to think something is wrong with their heart or they are about tohave another panic attack. In some cases, a heightened awareness(hypervigilance) of body functioning occurs during panic attacks,wherein any perceived physiological change is interpreted as a possiblelife threatening illness (i.e. extreme hypochondriasis).

Obsessive compulsive disorder is a type of anxiety disorder primarilycharacterized by repetitive obsessions (distressing, persistent, andintrusive thoughts or images) and compulsions (urges to perform specificacts or rituals). The OCD thought pattern may be likened tosuperstitions insofar as it involves a belief in a causativerelationship where, in reality, one does not exist. Often the process isentirely illogical; for example, the compulsion of walking in a certainpattern may be employed to alleviate the obsession of impending harm.And in many cases, the compulsion is entirely inexplicable, simply anurge to complete a ritual triggered by nervousness. In a minority ofcases, sufferers of OCD may only experience obsessions, with no overtcompulsions; a much smaller number of sufferers experience onlycompulsions.

The single largest category of anxiety disorders is that of phobia,which includes all cases in which fear and anxiety is triggered by aspecific stimulus or situation. Sufferers typically anticipateterrifying consequences from encountering the object of their fear,which can be anything from an animal to a location to a bodily fluid.

Post-traumatic stress disorder or PTSD is an anxiety disorder whichresults from a traumatic experience. Post-traumatic stress can resultfrom an extreme situation, such as combat, rape, hostage situations, oreven serious accident. It can also result from long term (chronic)exposure to a severe stressor, for example soldiers who endureindividual battles but cannot cope with continuous combat. Commonsymptoms include flashbacks, avoidant behaviors, and depression.

Eating Disorders

The compounds described herein can be used in a method described herein,for example in the treatment of a disorder described herein such as aneating disorder. Eating disorders feature disturbances in eatingbehavior and weight regulation, and are associated with a wide range ofadverse psychological, physical, and social consequences. An individualwith an eating disorder may start out just eating smaller or largeramounts of food, but at some point, their urge to eat less or morespirals out of control. Eating disorders may be characterized by severedistress or concern about body weight or shape, or extreme efforts tomanage weight or food intake. Eating disorders include anorexia nervosa,bulimia nervosa, binge-eating disorder, cachexia, and their variants.

Individuals with anorexia nervosa typically see themselves asoverweight, even when they are underweight. Individuals with anorexianervosa can become obsessed with eating, food, and weight control.Individuals with anorexia nervosa typically weigh themselves repeatedly,portion food carefully, and eat very small quantities of only certainfoods. Individuals with anorexia nervosa may engage in binge eating,followed by extreme dieting, excessive exercise, self-induced vomiting,or misuse of laxatives, diuretics, or enemas. Symptoms include extremelylow body weight, severe food restriction, relentless pursuit of thinnessand unwillingness to maintain a normal or healthy weight, intense fearof gaining weight, distorted body image and self-esteem that is heavilyinfluenced by perceptions of body weight and shape, or a denial of theseriousness of low body weight, lack of menstruation among girls andwomen. Other symptoms include the thinning of the bones, brittle hairand nails, dry and yellowish skin, growth of fine hair all over thebody, mild anemia, muscle wasting, and weakness, severe constipation,low blood pressure or slowed breathing and pulse, damage to thestructure and function of the heart, brain damage, multi-organ failure,drop in internal body temperature, lethargy, sluggishness, andinfertility.

Individuals with bulimia nervosa have recurrent and frequent episodes ofeating unusually large amounts of food and feel a lack of control overthese episodes. This binge eating is followed by behavior thatcompensates for the overeating such as forced vomiting, excessive use oflaxatives or diuretics, fasting, excessive exercise, or a combination ofthese behaviors.

Unlike anorexia nervosa, people with bulimia nervosa usually maintainwhat is considered a healthy or normal weight, while some are slightlyoverweight. But like people with anorexia nervosa, they typically feargaining weight, want desperately to lose weight, and are unhappy withtheir body size and shape. Usually, bulimic behavior is done secretlybecause it is often accompanied by feelings of disgust or shame. Thebinge eating and purging cycle can happen anywhere from several times aweek to many times a day. Other symptoms include chronically inflamedand sore throat, swollen salivary glands in the neck and jaw area, worntooth enamel, and increasingly sensitive and decaying teeth as a resultof exposure to stomach acid, acid reflux disorder and othergastrointestinal problems, intestinal distress and irritation fromlaxative abuse, severe dehydration from purging of fluids, electrolyteimbalance (that can lead to a heart attack or stroke).

Individuals with binge-eating disorder lose control over their eating.Unlike bulimia nervosa, periods of binge eating are not followed bycompensatory behaviors like purging, excessive exercise, or fasting.Individuals with binge-eating disorder often are overweight or obese.Obese individuals with binge-eating disorder are at higher risk fordeveloping cardiovascular disease and high blood pressure. They alsoexperience guilt, shame, and distress about their binge eating, whichcan lead to more binge eating.

Cachexia is also known as “wasting disorder,” and is an eating-relatedissue experienced by many cancer patients. Individuals with cachexia maycontinue to eat normally, but their body may refuse to utilize thevitamins and nutrients that it is ingesting, or they will lose theirappetite and stop eating. When an individual experiences loss ofappetite and stops eating, they can be considered to have developedanorexia nervosa.

Epilepsy

The compounds described herein can be used in a method described herein,for example in the treatment of a disorder described herein such asepilepsy, status epilepticus, or seizure, for example as described inWO2013/112605 and WO/2014/031792, the contents of which are incorporatedherein in their entirety.

Epilepsy is a brain disorder characterized by repeated seizures overtime. Types of epilepsy can include, but are not limited to generalizedepilepsy, e.g., childhood absence epilepsy, juvenile nyoclonic epilepsy,epilepsy with grand-mal seizures on awakening, West syndrome,Lennox-Gastaut syndrome, partial epilepsy, e.g., temporal lobe epilepsy,frontal lobe epilepsy, benign focal epilepsy of childhood.

Status epilepticus (SE)

Status epilepticus (SE) can include, e.g., convulsive statusepilepticus, e.g., early status epilepticus, established statusepilepticus, refractory status epilepticus, super-refractory statusepilepticus; non-convulsive status epilepticus, e.g., generalized statusepilepticus, complex partial status epilepticus; generalized periodicepileptiform discharges; and periodic lateralized epileptiformdischarges. Convulsive status epilepticus is characterized by thepresence of convulsive status epileptic seizures, and can include earlystatus epilepticus, established status epilepticus, refractory statusepilepticus, super-refractory status epilepticus. Early statusepilepticus is treated with a first line therapy. Established statusepilepticus is characterized by status epileptic seizures which persistdespite treatment with a first line therapy, and a second line therapyis administered. Refractory status epilepticus is characterized bystatus epileptic seizures which persist despite treatment with a firstline and a second line therapy, and a general anesthetic is generallyadministered. Super refractory status epilepticus is characterized bystatus epileptic seizures which persist despite treatment with a firstline therapy, a second line therapy, and a general anesthetic for 24hours or more.

Non-convulsive status epilepticus can include, e.g., focalnon-convulsive status epilepticus, e.g., complex partial non-convulsivestatus epilepticus, simple partial non-convulsive status epilepticus,subtle non-convulsive status epilepticus; generalized non-convulsivestatus epilepticus, e.g., late onset absence non-convulsive statusepilepticus, atypical absence non-convulsive status epilepticus, ortypical absence non-convulsive status epilepticus.

Compositions described herein can also be administered as a prophylacticto a subject having a CNS disorder e.g., a traumatic brain injury,status epilepticus, e.g., convulsive status epilepticus, e.g., earlystatus epilepticus, established status epilepticus, refractory statusepilepticus, super-refractory status epilepticus; non-convulsive statusepilepticus, e.g., generalized status epilepticus, complex partialstatus epilepticus; generalized periodic epileptiform discharges; andperiodic lateralized epileptiform discharges; prior to the onset of aseizure.

Seizure

A seizure is the physical findings or changes in behavior that occurafter an episode of abnormal electrical activity in the brain. The term“seizure” is often used interchangeably with “convulsion.” Convulsionsare when a person's body shakes rapidly and uncontrollably. Duringconvulsions, the person's muscles contract and relax repeatedly.

Based on the type of behavior and brain activity, seizures are dividedinto two broad categories: generalized and partial (also called local orfocal). Classifying the type of seizure helps doctors diagnose whetheror not a patient has epilepsy.

Generalized seizures are produced by electrical impulses from throughoutthe entire brain, whereas partial seizures are produced (at leastinitially) by electrical impulses in a relatively small part of thebrain. The part of the brain generating the seizures is sometimes calledthe focus.

There are six types of generalized seizures. The most common anddramatic, and therefore the most well known, is the generalizedconvulsion, also called the grand-mal seizure. In this type of seizure,the patient loses consciousness and usually collapses. The loss ofconsciousness is followed by generalized body stiffening (called the“tonic” phase of the seizure) for 30 to 60 seconds, then by violentjerking (the “clonic” phase) for 30 to 60 seconds, after which thepatient goes into a deep sleep (the “postictal” or after-seizure phase).During grand-mal seizures, injuries and accidents may occur, such astongue biting and urinary incontinence.

Absence seizures cause a short loss of consciousness (just a fewseconds) with few or no symptoms. The patient, most often a child,typically interrupts an activity and stares blankly. These seizuresbegin and end abruptly and may occur several times a day. Patients areusually not aware that they are having a seizure, except that they maybe aware of “losing time.”

Myoclonic seizures consist of sporadic jerks, usually on both sides ofthe body. Patients sometimes describe the jerks as brief electricalshocks. When violent, these seizures may result in dropping orinvoluntarily throwing objects.

Clonic seizures are repetitive, rhythmic jerks that involve both sidesof the body at the same time.

Tonic seizures are characterized by stiffening of the muscles.

Atonic seizures consist of a sudden and general loss of muscle tone,particularly in the arms and legs, which often results in a fall.

Seizures described herein can include epileptic seizures; acuterepetitive seizures; cluster seizures; continuous seizures; unremittingseizures; prolonged seizures; recurrent seizures; status epilepticusseizures, e.g., refractory convulsive status epilepticus, non-convulsivestatus epilepticus seizures; refractory seizures; myoclonic seizures;tonic seizures; tonic-clonic seizures; simple partial seizures; complexpartial seizures; secondarily generalized seizures; atypical absenceseizures; absence seizures; atonic seizures; benign Rolandic seizures;febrile seizures; emotional seizures; focal seizures; gelastic seizures;generalized onset seizures; infantile spasms; Jacksonian seizures;massive bilateral myoclonus seizures; multifocal seizures; neonatalonset seizures; nocturnal seizures; occipital lobe seizures; posttraumatic seizures; subtle seizures; Sylvan seizures; visual reflexseizures; or withdrawal seizures.

Tremor

The compounds described herein can be used in a method described herein,for example in the treatment of a disorder described herein such astremor.

Tremor is an involuntary, at times rhythmic, muscle contraction andrelaxation that can involve oscillations or twitching of one or morebody parts (e.g., hands, arms, eyes, face, head, vocal folds, trunk,legs).

Cerebellar tremor or intention tremor is a slow, broad tremor of theextremities that occurs after a purposeful movement. Cerebellar tremoris caused by lesions in or damage to the cerebellum resulting from,e.g., tumor, stroke, disease (e.g., multiple sclerosis, an inheriteddegenerative disorder).

Dystonic tremor occurs in individuals affected by dystonia, a movementdisorder in which sustained involuntary muscle contractions causetwisting and repetitive motions and/or painful and abnormal postures orpositions. Dystonic tremor may affect any muscle in the body. Dystonictremors occurs irregularly and often can be relieved by complete rest.

Essential tremor or benign essential tremor is the most common type oftremor. Essential tremor may be mild and nonprogressive in some, and maybe slowly progressive, starting on one side of the body but affect bothsides within 3 years. The hands are most often affected, but the head,voice, tongue, legs, and trunk may also be involved. Tremor frequencymay decrease as the person ages, but severity may increase. Heightenedemotion, stress, fever, physical exhaustion, or low blood sugar maytrigger tremors and/or increase their severity.

Orthostatic tremor is characterized by fast (e.g., greater than 12 Hz)rhythmic muscle contractions that occurs in the legs and trunkimmediately after standing. Cramps are felt in the thighs and legs andthe patient may shake uncontrollably when asked to stand in one spot.Orthostatic tremor may occurs in patients with essential tremor.

Parkinsonian tremor is caused by damage to structures within the brainthat control movement. Parkinsonian tremor is often a precursor toParkinson's disease and is typically seen as a “pill-rolling” action ofthe hands that may also affect the chin, lips, legs, and trunk. Onset ofparkinsonian tremor typically begins after age 60. Movement starts inone limb or on one side of the body and can progress to include theother side.

Physiological tremor can occur in normal individuals and have noclinical significance. It can be seen in all voluntary muscle groups.Physiological tremor can be caused by certain drugs, alcohol withdrawal,or medical conditions including an overactive thyroid and hypoglycemia.The tremor classically has a frequency of about 10 Hz.

Psychogenic tremor or hysterical tremor can occur at rest or duringpostural or kinetic movement. Patient with psychogenic tremor may have aconversion disorder or another psychiatric disease.

Rubral tremor is characterized by coarse slow tremor which can bepresent at rest, at posture, and with intention. The tremor isassociated with conditions that affect the red nucleus in the midbrain,classical unusual strokes.

Anesthesia Sedation

The compounds described herein can be used in a method described herein,for example to induce anesthesia or sedation. Anesthesia is apharmacologically induced and reversible state of amnesia, analgesia,loss of responsiveness, loss of skeletal muscle reflexes, decreasedstress response, or all of these simultaneously. These effects can beobtained from a single drug which alone provides the correct combinationof effects, or occasionally with a combination of drugs (e.g.,hypnotics, sedatives, paralytics, analgesics) to achieve very specificcombinations of results. Anesthesia allows patients to undergo surgeryand other procedures without the distress and pain they would otherwiseexperience.

Sedation is the reduction of irritability or agitation by administrationof a pharmacological agent, generally to facilitate a medical procedureor diagnostic procedure.

Sedation and analgesia include a continuum of states of consciousnessranging from minimal sedation (anxiolysis) to general anesthesia.

Minimal sedation is also known as anxiolysis. Minimal sedation is adrug-induced state during which the patient responds normally to verbalcommands. Cognitive function and coordination may be impaired.Ventilatory and cardiovascular functions are typically unaffected.

Moderate sedation/analgesia (conscious sedation) is a drug-induceddepression of consciousness during which the patient respondspurposefully to verbal command, either alone or accompanied by lighttactile stimulation. No interventions are usually necessary to maintaina patent airway. Spontaneous ventilation is typically adequate.Cardiovascular function is usually maintained.

Deep sedation/analgesia is a drug-induced depression of consciousnessduring which the patient cannot be easily aroused, but respondspurposefully (not a reflex withdrawal from a painful stimulus) followingrepeated or painful stimulation. Independent ventilatory function may beimpaired and the patient may require assistance to maintain a patentairway. Spontaneous ventilation may be inadequate. Cardiovascularfunction is usually maintained.

General anesthesia is a drug-induced loss of consciousness during whichthe patient is not arousable, even to painful stimuli. The ability tomaintain independent ventilatory function is often impaired andassistance is often required to maintain a patent airway. Positivepressure ventilation may be required due to depressed spontaneousventilation or drug-induced depression of neuromuscular function.Cardiovascular function may be impaired.

Sedation in the intensive care unit (ICU) allows the depression ofpatients' awareness of the environment and reduction of their responseto external stimulation. It can play a role in the care of thecritically ill patient, and encompasses a wide spectrum of symptomcontrol that will vary between patients, and among individualsthroughout the course of their illnesses. Heavy sedation in criticalcare has been used to facilitate endotracheal tube tolerance andventilator synchronization, often with neuromuscular blocking agents.

In some embodiments, sedation (e.g., long-term sedation, continuoussedation) is induced and maintained in the ICU for a prolonged period oftime (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 week, 3 weeks, 1month, 2 months). Long-term sedation agents may have long duration ofaction. Sedation agents in the ICU may have short elimination half-life.

Procedural sedation and analgesia, also referred to as conscioussedation, is a technique of administering sedatives or dissociativeagents with or without analgesics to induce a state that allows asubject to tolerate unpleasant procedures while maintainingcardiorespiratory function.

EXAMPLES

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. The synthetic andbiological examples described in this application are offered toillustrate the compounds, pharmaceutical compositions and methodsprovided herein and are not to be construed in any way as limiting theirscope.

Materials and Methods

The compounds provided herein can be prepared from readily availablestarting materials using the following general methods and procedures.It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. The choice of asuitable protecting group for a particular functional group as well assuitable conditions for protection and deprotection are well known inthe art. For example, numerous protecting groups, and their introductionand removal, are described in T. W. Greene and P. G. M. Wuts, ProtectingGroups in Organic Synthesis, Second Edition, Wiley, New York, 1991, andreferences cited therein.

The compounds provided herein may be isolated and purified by knownstandard procedures. Such procedures include (but are not limited to)recrystallization, column chromatography, HPLC, or supercritical fluidchromatography (SFC). The following schemes are presented with detailsas to the preparation of representative pyrazoles that have been listedherein. The compounds provided herein may be prepared from known orcommercially available starting materials and reagents by one skilled inthe art of organic synthesis. Exemplary chiral columns available for usein the separation/purification of the enantiomers/diastereomers providedherein include, but are not limited to, CHIRALPAK® AD-10, CHIRALCEL® OB,CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF,CHIRALCEL® OG, CHIRALCEL® OJ and CHIRALCEL® OK.

¹H-NMR reported herein (e.g., for intermediates) may be a partialrepresentation of the full NMR spectrum of a compound, e.g., a compounddescribed herein.

Exemplary general method for preparative HPLC: Column: Waters RBridgeprep 10 □m C18, 19*250 mm. Mobile phase: aectonitrile, water (NH₄HCO₃)(30 L water, 24 g NH₄HCO₃, 30 mL NH₃·H₂O). Flow rate: 25 mL/min

Exemplary general method for analytical HPLC: Mobile phase: A: water (10mM NH₄HCO₃), B: acetonitrileGradient: 5%-95% B in 1.6 or 2 min Flowrate: 1.8 or 2 mL/min; Column: XBridge C18, 4.6*50 mm, 3.5 m at 45 C.

Synthetic Procedures Example 1. General Procedure A: Preparation ofCompound 1

Step 1. Preparation of compound A2. Finely-ground potassium hydroxide(28.0 g, 165 mmol) was added to a solution of commercially available19-hydroxyandrost-4-ene-3,17-dione (A1, 50.0 g, 165 mmol) in anhydrous1,2-dimethoxyethane (500 mL) at 0° C. under nitrogen, after which methylsulfate (43.7 g, 208 mmol) was added portionwise. The mixture was slowlywarmed to room temperature, stirring for a total of 18 h, at which pointTLC analysis of the mixture (7:3 hexanes/ethyl acetate) indicatedcompletion of the reaction. The mixture was diluted with water (500 mL)and extracted with ethyl acetate (3×200 mL). The combined organicextracts were washed with saturated aqueous sodium chloride solution(100 mL), dried with anhydrous sodium sulfate and filtered. The solventswere removed under reduced pressure and the residue was purified bycolumn chromatography on silica gel, eluting with heptane/ethyl acetate(2:1), to provide A2 as a yellow solid (26.8 g, 50%).

Step 2. Preparation of compound A3. Triethyl orthoformate (6.2 mL, 37mmol) and p-toluenesulfonic acid (400 mg, 9.3 mmol) were added to asolution of compound A2 (9.9 g, 31.0 mmol) in anhydrous 1,4-dioxane (40mL) and anhydrous ethanol (30 mL) at room temperature under nitrogen,and the mixture was stirred for 1.5 h, at which point TLC analysis ofthe mixture (7:3 hexanes/ethyl acetate) indicated completion of thereaction. The mixture was diluted with saturated aqueous sodiumbicarbonate solution (100 mL), poured into water (300 mL) and extractedwith ethyl acetate (3×100 mL). The combined organic extract solventswere removed under reduced pressure and the residue was purified bycolumn chromatography on silica gel, eluting with heptane/ethyl acetate(2:1), to provide compound A3 as a white solid (7.0 g, 66%).

Step 3. Preparation of compound A4. A mixture of compound A3 (7.0 g,20.3) and palladium on carbon (3.0 g, 10 wt. %) in anhydrous ethylacetate (200 mL) was shaken under an atmosphere of hydrogen (1atmosphere) at room temperature for 1 h, at which point TLC analysis ofthe mixture (2:1 hexanes/ethyl acetate) indicated completion of thereaction. The atmosphere was exchanged for nitrogen and the mixture wasfiltered through a pad of Celite under reduced pressure, washing thefilter cake with ethyl acetate (50 mL). The filtrate solvents weretreated with 10% aqueous hydrochloric acid solution (100 mL) and thebiphasic mixture was stirred for 30 min. The mixture was extracted withethyl acetate (2×100 mL) and the combined organic extracts were washedsequentially with saturated aqueous sodium bicarbonate and saturatedaqueous sodium chloride solutions (50 mL each), dried with anhydroussodium sulfate and filtered. The solvents were removed under reducedpressure and the residue was purified by column chromatography on silicagel, eluting with heptane/ethyl acetate (4:1), to provide compound A4 asa colorless oil (3.9 g, 60%).

Step 4. Preparation of compound A5. Sodium hydride (1.7 g, 45 mmol, 60%in mineral oil) was added portionwise to a solution oftrimethylsulfoxonium iodide (9.1 g, 45 mmol) in anhydrous dimethylsulfoxide (100 mL) at room temperature under nitrogen, and the mixturewas stirred for 1 h, after which a solution of compound A4 (9.5 g, 29.8mmol) in anhydrous dimethyl sulfoxide (100 mL) was added. The resultingmixture was stirred at room temperature for 12 h, at which point TLCanalysis of the mixture (7:3 hexanes/ethyl acetate) indicated completionof the reaction. The mixture was diluted with water (500 mL) andextracted with methyl tert-butyl ether (2×300 mL). The combined organicextracts were washed with water (2×300 mL), dried with anhydrousmagnesium sulfate and filtered. The solvents were removed under reducedpressure to provide compound A5 as a colorless oil that was used in thenext step without further purification (7.5 g, 76%).

Step 5. Preparation of compound A6. Lithium aluminum hydride (67 mL, 67mmol, 1 M solution in tetrahydrofuran) was added to a solution of crudecompound A5 (7.5 g, 22.2 mmol) in anhydrous tetrahydrofuran (5 mL) at 0°C. under nitrogen, after which the mixture was slowly warmed to roomtemperature, stirring for a total of 2 h, at which point TLC analysis ofthe mixture (7:3 hexanes/ethyl acetate) indicated completion of thereaction. The mixture was carefully treated with water (10 mL) followedby saturated aqueous sodium chloride solution (30 mL) and extracted withethyl acetate (3×50 mL). The combined organic extracts were dried withanhydrous magnesium sulfate, filtered and the solvents were removedunder reduced pressure to provide compound A6 as a colorless oil thatwas used in the next step without further purification (5.5 g, 74%):LCMS m/z 319 [M+H−H₂O]⁺.

Step 6. Preparation of compound A7. Pyridinium chlorochromate (4.0 g, 19mmol) was added in one portion to a solution of crude compound A6 (4.2g, 12.5 mmol) in anhydrous dichloromethane (100 mL) at 0° C. undernitrogen. The mixture was slowly warmed to room temperature, stirringfor a total of 3 h, at which point TLC analysis of the mixture (7:3hexanes/ethyl acetate) indicated completion of the reaction. The solidswere removed by filtration and the filtrate solvents were removed underreduced pressure. The residue was purified by column chromatography onsilica gel, eluting with heptane/ethyl acetate (7:3), to providecompound A7 as a light yellow solid (2.1 g, 50%): LCMS m/z 317[M+H−H₂O]⁺.

Step 7. Preparation of compound A8. Potassium tert-butoxide (4.3 g, 38mmol) was added to a mixture of ethyltriphenylphosphonium bromide (14.2g, 38 mmol) in anhydrous tetrahydrofuran (30 mL) at room temperatureunder nitrogen, after which the mixture was heated to 80° C. and stirredfor 1 h. A solution of compound A7 (3.1 g, 9.3 mmol) in anhydroustetrahydrofuran (10 mL) was added, after which stirring at 80° C. wascontinued for 2 h, at which point TLC analysis of the mixture (7:3hexanes/ethyl acetate) indicated completion of the reaction. The cooledmixture was diluted with water (30 mL) and saturated aqueous sodiumchloride solution (20 mL) and extracted with ethyl acetate (2×100 mL).The combined organic extract solvents were removed under reducedpressure and the residue was purified by column chromatography on silicagel, eluting with heptane/ethyl acetate (7:3), to provide compound A8 asan off-white solid (2.0 g, 66%): LCMS m/z 329 [M+H−H₂O]⁺.

Step 8. Preparation of compound A9. Borane-tetrahydrofuran complex (20.0mL, 20 mmol, 1 M solution in tetrahydrofuran) was added to a solution ofcompound A8 (2.0 g, 5.8 mmol) in anhydrous tetrahydrofuran (15 mL) at 0°C. under nitrogen, after which the mixture was slowly warmed to roomtemperature, stirring for a total of 1 h. The mixture was cooled in anice bath and 10% aqueous sodium hydroxide solution (12 mL) was slowlyadded, followed by 30% aqueous hydrogen peroxide solution (12 mL). Theresulting mixture was warmed to room temperature and stirred for 1 h, atwhich point TLC analysis of the mixture (7:3 hexanes/ethyl acetate)indicated completion of the reaction. The mixture was extracted withdichloromethane (2×100 mL) and the combined organic extracts were washedwith saturated aqueous sodium chloride solution (25 mL), dried withsodium sulfate and filtered. The solvents were removed under reducedpressure to provide crude compound A9 as a white solid that was used inthe next step without further purification (2.5 g, >99%).

Step 9. Preparation of compound 1. Pyridinium chlorochromate (2.4 g, 11mmol) was added in one portion to a solution of crude compound A9 (2.5g, 6.9 mmol) in anhydrous dichloromethane (30 mL) at 0° C. undernitrogen. The mixture was slowly warmed to room temperature, stirringfor a total of 2 h, at which point TLC analysis of the mixture (7:3hexanes/ethyl acetate) indicated completion of the reaction. The solidswere removed by filtration and the filtrate solvents were removed underreduced pressure. The residue was purified by column chromatography onsilica gel, eluting with heptane/ethyl acetate (7:3), to provide 1 as anoff-white solid (1.5 g, 61%). ¹H NMR: (500 MHz, CDCl₃), δ (ppm), 3.49(AB, 1H), 3.39 (AB, 1H), 3.31 (s, 3H), 2.56 (t, 1H), 2.14 (s, 3H), 1.25(s, 3H), 0.65 (s, 3H).

Example 2. Preparation of Compound 2

Step 1. Preparation of compound A11. Prepared according GeneralProcedure A, Step 1 from 1 (10.0 g, 33 mmol) and ethyl sulfate (17.3 mL,132 mmol), with purification by column chromatography on silica gel toprovide compound A11 as a yellow oil (4.6 g, 42%).

Step 2. Preparation of compound A12. Prepared according GeneralProcedure A, Step 2 from compound A11 (4.6 g, 14 mmol) to provide crudecompound A12 as a yellow oil that was used in the next step withoutfurther purification.

Step 3. Preparation of compound A13. Prepared according GeneralProcedure A, Step 3 from crude compound A12, with purification by columnchromatography on silica gel to provide compound A13 as a yellow oil(1.5 g, 31%).

Step 4. Preparation of compound A14. Prepared according GeneralProcedure A, Step 4 from compound A13 (1.7 g, 5.1 mmol) to provide crudecompound A14 as a yellow oil that was used in the next step withoutfurther purification.

Step 5. Preparation of compound A15. Prepared according GeneralProcedure A, Step 5 from crude compound A14 to provide crude compoundA15 as a yellow oil that was used in the next step without furtherpurification.

Step 6. Preparation of compound A16. Prepared according GeneralProcedure A, Step 6 from crude compound A15, with purification by columnchromatography on silica gel to provide compound A16 as an off-whitesolid (751 mg, 40%).

Step 7. Preparation of compound A17. Prepared according GeneralProcedure A, Step 7 from compound A16 (750 mg, 2.2 mmol), withpurification by column chromatography on silica gel to provide compoundA17 as a colorless oil (757 mg, 97%).

Step 8. Preparation of compound A18. Prepared according GeneralProcedure A, Step 8 from compound A17 (757 mg, 2.1 mmol), to providecrude compound A18 as a yellow oil that was used in the next stepwithout further purification.

Step 9. Preparation of 2. Prepared according General Procedure A, Step 9from crude compound A18, with purification by column chromatography onsilica gel to provide 2 as a white solid (515 mg, 65%): mp 106-107° C.;¹HNMR (500 MHz, CDCl₃) δ 3.51 (d, 1H), 3.43-3.36 (m, 3H), 2.53 (t, 1H),2.18-1.96 (m, 6H), 1.74-0.92 (m, 25H), 0.84-0.82 (m, 1H), 0.62 (s, 3H)ppm; ESI MS m/z 359 [M+H−H₂O]⁺.

Example 3. General Procedure C: Preparation of Compound 3

Step 1. Preparation of compound B2. A mixture of commercially available19-hydroxyandrost-4-ene-3,17-dione (A1, 13.6 g, 45 mmol) and palladiumon carbon (3.2 g, 10 wt. %) in anhydrous tetrahydrofuran (150 mL) wasshaken under an atmosphere of hydrogen (50 psi) at room temperature for12 h, at which point TLC analysis of the mixture (2:1 hexanes/ethylacetate) indicated completion of the reaction. The atmosphere wasexchanged for nitrogen and the mixture was filtered through a pad ofCelite under reduced pressure, washing the filter cake with ethanol. Thefiltrate solvents were removed under reduced pressure to provide B2 as awhite solid that was used in the next step without further purification(13.0 g, 95%): LCMS m/z 305 [M+H]⁺.

Step 2. Preparation of compound B3. Pyridine hydrochloride (750 mg, 6.5mmol) was added to a solution of crude compound B2 (15.0 g, 49 mmol) inethylene glycol (65 mL) and anhydrous toluene (180 mL) at roomtemperature under nitrogen. The mixture was heated at reflux for 12 hwith water removal by Dean-Stark apparatus, at which point TLC analysisof the mixture (2:1 hexanes/ethyl acetate) indicated completion of thereaction. The solvents were removed from the cooled mixture underreduced pressure and the residue was treated with saturated aqueoussodium chloride solution (50 mL) and extracted with ethyl acetate (3×50mL). The combined organic extracts were washed with saturated aqueoussodium chloride solution (3×10 mL), dried with anhydrous sodium sulfateand filtered. The solvents were removed under reduced pressure toprovide compound B3 as a colorless oil that was used in the next stepwithout further purification (20.3 g, >99%): ¹H NMR (300 MHz, CDCl₃) δ4.11-3.81 (m, 8H), 3.60-3.54 (m, 1H), 2.05-1.92 (m, 3H), 1.81-163 (m,4H), 1.59-1.35 (m, 12H), 1.28-1.12 (m, 5H), 0.8 (s, 3H) ppm; LCMS m/z393 [M+H]⁺.

Step 3. Preparation of compound B4. A solution of crude compound B3(20.3 g, 49 mmol) in anhydrous tetrahydrofuran (120 mL) was addeddropwise to a suspension of sodium hydride (7.9 g, 197 mmol, 60% inmineral oil) in anhydrous tetrahydrofuran (120 mL) at 0° C. undernitrogen, after which the mixture was stirred at 0° C. for 30 min.Iodomethane (15.3 mL, 246 mmol) was added dropwise, after which themixture was heated to 35° C. and stirred for 3 h, at which point TLCanalysis of the mixture (3:1 hexanes/ethyl acetate) indicated completionof the reaction. The cooled mixture was treated with saturated ammoniumchloride solution (100 mL) and extracted with ethyl acetate (2×50 mL).The combined organic extracts were washed with saturated aqueous sodiumchloride solution (2×20 mL), dried with anhydrous sodium sulfate andfiltered. The solvents were removed under reduced pressure to providecrude compound B4 as a yellow oil that was used in the next step withoutfurther purification (25.6 g, >99%): LCMS m/z 407 [M+H]⁺.

Step 4. Preparation of compound B5. A mixture of crude compound B4 (25.5g, 49 mmol) in tetrahydrofuran (150 mL) and acetone (90 mL) at roomtemperature was treated with 2N HCl (123 mL) and the mixture was stirredfor 16 h, at which point TLC analysis of the mixture (2:1 hexanes/ethylacetate) indicated completion of the reaction. The reaction mixture wasadjusted to pH 8 with slow addition of saturated aqueous sodiumbicarbonate solution and extracted with ethyl acetate (3×125 mL). Thecombined organic extracts were washed with saturated aqueous sodiumchloride solution (2×20 mL), dried with anhydrous sodium sulfate andfiltered. The solvents were removed under reduced pressure and theresidue was purified by column chromatography on silica gel, elutingwith hexanes/ethyl acetate (2:1), to provide compound B5 as a whitesolid (10.6 g, 67%): ¹H NMR (300 MHz, CDCl₃) δ 3.62-3.59 (m, 1H),3.36-3.33 (m, 4H), 2.67-2.63 (m, 1H), 2.58-2.45 (m, 1H), 2.42-2.27 (m,3H), 2.25-1.84 (m, 6H), 1.71-1.23 (m, 11H), 0.89 (s, 3H) ppm; LCMS m/z319 [M+H]⁺.

Step 5. Preparation of compound B6. Iodine (84 mg, 0.3 mmol) was addedto a solution of compound B5 (10.6 g, 33 mmol) in anhydrous methanol(200 mL) at room temperature under nitrogen, after which the mixture washeated to 60° C. and stirred for 90 min, at which point TLC analysis ofthe mixture (2:1 hexanes/ethyl acetate) indicated completion of thereaction. The cooled mixture was treated with 1N sodium hydroxidesolution (200 mL) and extracted with hexanes/ethyl acetate (3:1, 3×100mL). The combined organic extracts were washed with saturated aqueoussodium chloride solution (2×25 mL), dried with anhydrous sodium sulfateand filtered. The solvents were removed under reduced pressure toprovide compound B6 as a colorless oil that was used in the next stepwithout further purification (13.8 g, >99%); LCMS m/z 365 [M+H]⁺.

Step 6. Preparation of compound B7. Potassium tert-butoxide (11.2 g, 100mmol) was added to a mixture of ethyltriphenylphosphonium bromide (36.9g, 100 mmol) in anhydrous tetrahydrofuran (150 mL) at room temperatureunder nitrogen, after which the mixture was heated to 60° C. and stirredfor 4 h. A solution of compound B6 (13.8 g, 33 mmol) in anhydroustetrahydrofuran (100 mL) was added, after which stirring at 60° C. wascontinued for 18 h. The cooled mixture was diluted with water (200 mL)and hexanes (100 mL) and extracted with ethyl acetate (3×100 mL). Thecombined organic extracts were washed with saturated aqueous sodiumchloride solution (2×25 mL), treated with 2N HCl (100 mL) and stirred atroom temperature for 3 h. The resulting mixture was washed withsaturated aqueous sodium bicarbonate and saturated aqueous sodiumchloride solutions, dried with sodium sulfate and filtered. The solventswere removed under reduced pressure and the residue was purified bycolumn chromatography on silica gel, eluting with hexanes/ethyl acetate(9:1), to provide compound B7 as a colorless oil (9.2 g, 84%): LCMS m/z331 [M+H]⁺.

Step 7. Preparation of compound B8.Bis(2,6-di-tert-butyl-4-methylphenoxide)methylaluminum (40.6 mL, 16mmol, 0.4 M in toluene) was added in one portion to a solution ofcompound B7 (1.8 g, 5.4 mmol) in anhydrous toluene (20 mL) at −78° C.under nitrogen, after which the mixture was stirred for 10 min.Methylmagnesium bromide (11.6 mL, 16 mmol, 1.4 M intetrahydrofuran/toluene) was added dropwise, after which the mixture wasstirred at −78° C. for 1 h. The mixture was warmed to ice bathtemperature and slowly treated with 2N HCl (60 mL), warmed to roomtemperature and extracted with ethyl acetate (3×50 mL). The combinedorganic extracts were washed with saturated aqueous sodium chloridesolution (2×20 mL), dried with sodium sulfate and filtered. The solventswere removed under reduced pressure and the residue was purified bycolumn chromatography on silica gel, eluting with hexanes/ethyl acetate(2:1), to provide crude compound B8 as a white semi-solid (1.5 g, 91%);LCMS m z 347 [M+H]⁺.

Step 8. Preparation of compound B9. Borane-tetrahydrofuran complex (27.6mL, 27.6 mmol, 1.0 M solution in tetrahydrofuran) was added to asolution of compound B8 (2.4 g, 6.9 mmol) in anhydrous tetrahydrofuran(24 mL) at 0° C. under nitrogen, after which the mixture was slowlywarmed to room temperature, stirring for a total of 4 h. The mixture wascooled in an ice bath and 10% aqueous sodium hydroxide solution (20 mL)was slowly added, followed by 30% aqueous hydrogen peroxide solution (20mL). The resulting mixture was warmed to room temperature and stirredfor 1 h and then treated with saturated aqueous sodium chloride solution(100 mL) and extracted with dichloromethane (3×100 mL). The combinedorganic extracts were washed with saturated aqueous sodium chloridesolution (25 mL), dried with sodium sulfate and filtered. The solventswere removed under reduced pressure to provide crude compound B9 as awhite solid that was used in the next step without further purification(2.7 g, >99%); LCMS m/z 365 [M+H]⁺.

Step 9. Preparation of 3. Pyridinium chlorochromate (6.0 g, 28 mmol) wasadded in one portion to a solution of compound B9 (2.7 g, 6.9 mmol) indichloromethane (100 mL) at 0° C. under nitrogen, after which themixture was slowly warmed to room temperature, stirring for a total of16 h. The solids were removed by filtration and the filtrate solventswere removed under reduced pressure. The residue was semi-purified bycolumn chromatography on silica gel, eluting with hexanes/ethyl acetate(1:1), followed by further purification by reverse phase preparativeHPLC to provide 3 as a white solid (2.15 g, 86%): mp 142-144° C.; ¹HNMR(300 MHz, CDCl₃) δ 3.55 (d, 1H), 3.33 (s, 3H), 3.19 (d, 1H), 2.53 (t,1H), 2.21-2.11 (m, 4H), 2.08-1.87 (m, 3H), 2.14-1.91 (m, 7H), 1.77-1.36(m, 16H), 1.28 (s, 3H), 1.26-1.07 (m, 2H), 0.60 (s, 3H) ppm; LCMS m/z345 [M+H−H₂O]⁺.

Example 4. General Procedure D: Preparation of 4

Step 1. Preparation of compound B12. 2,2-Dimethylpropane-1,3-diol (6.1g, 59 mmol) and p-toluenesulfonic acid (931 mg, 4.9 mmol) were added toa solution of Bit (20.0 g, 49.0 mmol) in anhydrous 1,2-dimethoxyethane(300 mL) at room temperature under nitrogen, and the mixture was stirredfor 12 h, at which point TLC analysis of the mixture (7:3 hexanes/ethylacetate) indicated completion of the reaction. The solvents were removedunder reduced pressure and the residue was purified by columnchromatography on silica gel, eluting with heptane/ethyl acetate (1:1),to provide compound B12 as an off-white solid (10.5 g, 43%): LCMS m/z495 [M+H]⁺.

Step 2. Preparation of compound B13. Potassium carbonate (16.4 g, 119mmol) was added to a solution of compound B12 (9.8 g, 19.8 mmol) inanhydrous methanol (150 mL) and anhydrous tetrahydrofuran (70 mL) atroom temperature under nitrogen, after which the mixture was heated to50° C. to stir for 12 h, at which point TLC analysis of the mixture (7:3hexanes/ethyl acetate) indicated completion of the reaction. Thesolvents were removed under reduced pressure and the residue was treatedwith water (100 mL) and extracted with ethyl acetate (3×100 mL). Thecombined organic extracts were washed with saturated aqueous sodiumchloride solution (40 mL), dried with sodium sulfate and filtered. Thesolvents were removed under reduced pressure and the residue waspurified by column chromatography on silica gel, eluting withhexanes/ethyl acetate (1:4), to provide compound B13 as an off-whitesolid (5.8 g, 75%): LCMS m/z 391 [M+H]⁺.

Step 3. Preparation of compound B14. Finely-ground potassium hydroxide(4.7 g, 85 mmol) was added to a solution of compound B13 (5.5 g, 14.1mmol) in anhydrous 1,2-dimethoxyethane (200 mL) at 0° C. under nitrogen,after which ethyl sulfate (8.7 g, 56 mmol) was added portionwise. Themixture was slowly warmed to room temperature and then heated to 40° C.,stirring for a total of 12 h, at which point TLC analysis of the mixture(7:3 hexanes/ethyl acetate) indicated completion of the reaction. Themixture was diluted with water (200 mL) and extracted with ethyl acetate(3×200 mL). The combined organic extracts were washed with saturatedaqueous sodium chloride solution (100 mL), dried with anhydrous sodiumsulfate and filtered. The solvents were removed under reduced pressureand the residue was semi-purified by column chromatography on silicagel, eluting with heptane/ethyl acetate (4:1), to provide semi-purecompound B14 as a yellow oil that was used in the next step withoutfurther purification: LCMS m/z 419 [M+H]⁺.

Step 4. Preparation of compound B15. Potassium tert-butoxide (5.02 g, 44mmol) was added to a mixture of ethyltriphenylphosphonium bromide (16.5g, 44 mmol) in anhydrous tetrahydrofuran (150 mL) at room temperatureunder nitrogen, after which the mixture was heated to 60° C. and stirredfor 12 h. A solution of compound B14 (6.2 g, 14.8 mmol) in anhydroustetrahydrofuran (50 mL) was added, after which stirring at 60° C. wascontinued for 18 h. The cooled mixture was diluted with water (200 mL)and saturated aqueous sodium chloride solution (50 mL) and extractedwith ethyl acetate (3×100 mL). The combined organic extracts were washedwith saturated aqueous sodium chloride solution (50 mL), dried withsodium sulfate and filtered. The solvents were removed under reducedpressure and the residue was purified by column chromatography on silicagel, eluting with hexanes/ethyl acetate (9:1), to provide compound B15as a light yellow oil (3.6 g, 57%): LCMS m/z 431 [M+H]⁺.

Step 5. Preparation of compound B16. A mixture of crude compound B15(3.5 g, 8.1 mmol) in tetrahydrofuran (10 mL) at room temperature wastreated with 4N HCl (10 mL), after which the mixture was heated to 50°C. and stirred for 4 h, at which point TLC analysis of the mixture (2:1hexanes/ethyl acetate) indicated completion of the reaction. Thesolvents were removed under reduced pressure and the residue wassemi-purified by column chromatography on silica gel, eluting withheptane/ethyl acetate (1:19), to provide semi-pure compound B16 as ayellow oil: LCMS m/z 345 [M+H]⁺.

Step 6. Preparation of compound B17. Prepared according GeneralProcedure C, Step 7 from semi-pure compound B16 (500 mg, 1.4 mmol) toprovide semi-pure compound B17 as a yellow oil that was used in the nextstep without further purification: LCMS m/z 361 [M+H]⁺.

Step 7. Preparation of compound B18. Prepared according GeneralProcedure C, Step 8 from semi-pure compound B17 to provide semi-purecompound B18 as a colorless oil that was used in the next step withoutfurther purification: LCMS m/z 379 [M+H]⁺.

Step 9. Preparation of 4. Prepared according General Procedure C, Step 9from semi-pure compound B18, with semi-purification by columnchromatography on silica gel followed by further purification by reversephase preparative HPLC to provide 4 as an off-white solid (110 mg, 22%):mp 46-48° C.; ¹HNMR (300 MHz, CDCl₃) δ 3.57 (d, 1H), 3.44 (q, 2H), 3.21(d, 1H), 2.53 (t, 1H), 2.14-1.87 (m, 8H), 1.83-1.41 (m, 13H), 1.28-1.12(m, 11H), 0.59 (s, 3H) ppm; LCMS m/z 359 [M+H−H₂O]⁺.

Example 5. Preparation of 5

Step 1. Preparation of compound B20. Prepared according GeneralProcedure C, Step 3 from compound B13 (4.5 g, 11.4 mmol) and isopropylsulfate (11.4 mL, 68.7 mmol), with purification by column chromatographyon silica gel to provide compound B20 as a light yellow oil (1.6 g,32%): LCMS m/z 433 [M+H]⁺.

Step 2. Preparation of compound B21. Prepared according GeneralProcedure C, Step 4 from compound B20 (1.6 g, 3.7 mmol) to provide crudecompound B21 as a light yellow oil: LCMS m/z 445 [M+H]⁺.

Step 3. Preparation of compound B22. Prepared according GeneralProcedure C, Step 5 from crude compound B21, with purification by columnchromatography on silica gel to provide compound B22 as a colorless oil(1.1 g, 22%): LCMS m/z 359 [M+H]⁺.

Step 4. Preparation of compound B23. Prepared according GeneralProcedure C, Step 6 from compound B22 (1.1 g, 3.1 mmol) to provide crudecompound B23 as a colorless oil: LCMS m/z 359 [M+H]⁺.

Step 5. Preparation of compound B24. Prepared according GeneralProcedure C, Step 7 from crude compound B23 to provide crude compoundB24 as a white solid: LCMS m/z 393 [M+H]⁺.

Step 6. Preparation of 5. Prepared according General Procedure C, Step 8from crude compound B24, with semi-purification by column chromatographyon silica gel followed by further purification by reverse phasepreparative HPLC to provide 5 as a white solid (340 mg, 36%): mp 44-46°C.; ¹HNMR (300 MHz, CDCl₃) δ 3.53 (d, 1H), 3.47-3.33 (m, 1H), 3.22 (d,1H), 2.53 (t, 1H), 2.21-1.88 (m, 8H), 1.83-1.31 (m, 9H), 1.29-1.09 (m,18H), 0.60 (s, 3H) ppm; LCMS m/z 373 [M+H−H₂O]⁺.

Example 6. Preparation of 6

Step 1. Preparation of compound C2. Compound C1 (10.0 g, 33 mmol) wasdissolved in 100 mL of THF. Dihydropyran (25 ml, 270 mmol) and PPTS(4.16, 16 mmol) was added and the resultant reaction mixture wasvigorously stirred for 15 h at room temperature. Upon concentrationunder reduced pressure, the reaction mixture was taken up in EtOAc (500mL), washed with water (300 mL) and brine (300 mL), dried over sodiumsulfate and concentrated under reduced pressure, The residue waspurified by chromatography on silica gel (eluant: petroleumether/EtOAc=10/1˜3/1) to afford compound C2 12.52 g (97.65%). LC-MS:rt=1.65 min, m/z=409.0 [M+Na]+

Step 2. Preparation of compound C3. Lithium metal (3.0 g, 0.4 mmol) wereadded to condensed ammonia (500 ml) in a three neck flask at −70° C.Then a solution of compound C2 (5.0 g, 13 mmol) and tert-BuOH (0.95 g,13 mmol) in anhydrous tetrahydrofuran (100 mL) was added dropwise andstirred for 0.8 hours. Ammonium chloride (30.0 g) was added to quenchthe reaction and the ammonia was left to evaporate overnight. Theresidue was extracted with EtOAc (300 mL). The organic layers werewashed with saturated NaCl solution (2×200 mL), dried over Na2SO4 andconcentrated under reduced pressure, The residue was purified bychromatography on silica gel (eluant: petroleum ether/EtOAc=10/1˜2/1) toafford 2.0 g of compound C3 (39.60%). LC-MS: rt=1.68 min, m/z=413.3[M+Na]+

Step 3. Preparation of compound C4. Me3SOI (16.9 g, 76.80 mmol) wasdissolved in 80 mL of DMSO and NaH (1.84 g, 76.80 mmol) was added. Themixture was stirred at room temperature for 1 hour, then compound C3(6.0 g, 15.36 mmol) dissolved in 60 mL of DMSO was added. The solutionwas stirred at room temperature overnight. Water (10 mL) was then addedto the reaction mixture. The aqueous reaction mixture was extracted withEtOAc (300 mL×3). The extracts were dried over Na2SO4, filtered,concentrated. The crude compound C4 was directly used in the next stepwithout further purification.

Step 4. Preparation of compound C5. The crude compound C4 was slowlyadded into a suspension of LiAlH4 (1.75 g, 51 mmol) in 100 ml of dry THFat 0° C. The mixture was stirred at room temperature for 2 h, then 2.1 gof 15% aq NaOH was slowly added to quench the reaction. The reactionmixture extracted with EtOAc (200 mL×3). The organic layers were driedover MgSO4, filtered, and concentrated. The crude compound C5 wasdirectly used in the next step without further purification.

Step 5. Preparation of compound C6. The crude compound C5 was dissolvedin 100 ml of dry CH2Cl2, and 4.0 g of PCC was added at 0° C. Then themixture was stirred at room temp for 6 h. The reaction mixture was thenfiltered, concentrated, and purified by flash chromatography on silicagel using 10/1 ˜3/1 petroleum ether: ethyl acetate=10/1-3/1 elution togive compound C6, 3.10 g (50.89%, three-step yield).

Step 6. Preparation of compound C7. To a suspension ofEthyltriphenylphosphonium bromide (14.20 g, 38.3 mmol) in dry THF (40mL) was added KOtBu (4.30 g, 38.3 mmol) under N2 atmosphere. The mixturewas heated at reflux for 1 hour, during which time the mixture turnedbright orange. Then compound C6 (3.1 g, 7.66 mmol) in dry THF (25 mL)was added to the above refluxing solution and stirred at refluxovernight. After cooling to room temperature, the solution was pouredinto brine (100 mL). The aqueous solution was extracted with ethylacetate (100 mL×3). The extracts were washed with brine (30 mL×2), driedover Na2SO4, filtered, concentrated and purified by columnchromatography on silica gel (petroleum ether/EtOAC from 10/1 to 4/1) togive compound C7 2.2 g (68.97%) as white solid. Furthermore, the C-3isomer (0.30 g, 9.63%) was also obtained.

Step 7. Preparation of compound C8. To a solution of compound C7 (3 g,7.2 mmol) in dry THF (20 mL) was added borane-tetrahydrofuran complex(29 mL of 1.0 M solution in THF) and the reaction mixture was stirred atambient temperature for 1 hour. 10% aqueous NaOH (20 mL) was slowlyadded. The mixture was cooled in ice and 30% aqueous solution of H202(20 mL) was slowly added. The mixture was stirred at ambient temperaturefor 1 hour and then extracted with CH2Cl2 (3×100 mL). The combinedCH2Cl2 extracts were washed with 10% aqueous Na2S203 (50 mL), which wasdirectly used in the next step without further purification.

Step 7. Preparation of compound 6. The combined CH₂Cl₂ extracts of thecompound C8 of last step was used without further purification. 3.5 g ofPCC was added at 0° C. Then the mixture was stirred at room temperaturefor 6 h, The mixture was filtered, concentrated, and purified by flashchromatography on silica gel using 12/1˜7/1(petroleum ether:ethylacetate) elution to give 1.28 g of compound 6 (41.23% two steps). LC-MS:rt=1.90 min, m/z=455.3[M+Na]+. 1HNMR (500 MHz, CDCl3) δ(ppm): 4.57&4.53(1H, t), 3.96&3.87 (1H) 3.82 (1H, t), 3.56˜3.53 (1H), 3.44&3.27 (1H,AB), 2.53 (1H, t), 2.12&2.11 (3H, s), 1.22&1.21 (3H, s), 0.64&0.61 (1H,s).

Example 7. Preparation of 7

Step 1. Preparation of compound C9. Compound 6 (1.28 g, 2.96 mmol) wasdissolved in 50 mL of dry MeOH and 100 mg of PTSA was added. Thereaction mixture was stirred at room temperature overnight. The reactionmixture was then concentrated under reduced pressure. This productmixture was separated by flash chromatography on silica gel using8/1-2/1 (pertroleum ether:EtOAc) elution to give 674 mg of compound C9(65.32%). LC-MS: rt=1.90 min, m/z=331.3[M−H2O+H]⁺, m/z=349.2[M+H]⁺.¹HNMR (500 MHz, CDCl3) δ(ppm): 3.89 (1H, AB), 3.72 (1H, AB), 2.53 (1H,t), 2.11 (3H, s), 1.22 (3H, s), 0.64 (3H, s). ¹³CNMR (125.77 MHz, CDCl3)δ(ppm): 209.78, 69.68, 63.80, 60.12, 57.07, 54.39, 44.36, 42.04, 41.18,39.62, 39.31, 36.05, 35.39, 31.85, 31.68, 31.54, 28.04, 27.91, 24.39,22.86, 22.75, 13.72.

Step 2. Preparation of compound 7. 30 mg of compound C9 was dissolved intoluene (3 ml) and isocyanatoethane (60 mg, 0.9 mmol) was added. Thereaction mixture was heated to reflux overnight in a pressure sealedtube. After cooling to room temperature, the solvent was removed underreduced pressure and the residue was purified by silica gel (EA/PE=1:4).10 mg of compound 7 was isolated as a white residue, (yield 25%). ¹HNMR(400 MHz, MeOD) δ (ppm): 4.26 (1H, AB), 4.03 (1H, AB), 3.02 (2H, q),2.53 (1H, t), 2.01 (3H, s), 1.08 (3H, s), 0.99 (3H, t), 0.51 (3H, s).

Example 8. Preparation of 8

Step 1. Preparation of compound A10. Hydrogen bromide (3 drops, 48% inwater) was added to a solution of 1 (1.4 g, 3.9 mmol) in anhydrousmethanol (150 mL) at room temperature in the dark under nitrogen, afterwhich bromine (0.4 mL, 7.7 mmol) was added. The mixture was stirred for1 h, at which point TLC analysis of the mixture (7:3 hexanes/ethylacetate) indicated completion of the reaction. The mixture was pouredinto ice-water (100 mL), treated with saturated aqueous sodiumbicarbonate solution (30 mL) and extracted with ethyl acetate (2×60 mL).The combined organic extracts were washed with saturated aqueous sodiumbicarbonate solution (4×100 mL) and saturated aqueous sodium chloridesolution (50 mL), dried with magnesium sulfate and filtered. Thesolvents were removed under reduced pressure and the residue waspurified by column chromatography on silica gel, eluting withheptane/ethyl acetate (1:1), to provide compound A10 as a colorlesssemi-solid (1.2 g, 71%): LCMS m/z 441 [M+H]⁺.

Step 2. Preparation of compound 8. To a solution of compound A10 (60 mg,crude) in DMF/H₂O (2 mL/1 mL) was added NaOH (30 mg, 0.7 mmol). Theresulting solution was stirred at room temperature for 30 min. Then TLCshowed the reaction was complete. The solution was diluted with EtOAc(30 mL) and washed with brine (15 mL×2). Dried over Na₂SO₄ andconcentrated, the residue was purified by column chromatography (silicagel, EtOAc/PE=3:1) to give compound 8 (10 mg, 20%) as a white solid. ¹HNMR: (500 MHz, CDCl₃), δ (ppm), 4.25-4.14 (m, 2H), 3.48 (AB, 1H), 3.38(AB, 1H), 3.30 (s, 3H), 2.47 (t, 1H), 1.25 (s, 3H), 0.67 (s, 3H).

Example 9. Preparation of 9

Step 1. Preparation of compound A20. To a solution of A19 (1 g, 3.00mmol) in dry THF (10 mL) was added NaH (60%, 1.19 g, 30 mmol) inportions carefully. The suspension was stirred at 50° C. for 1 hour, and1-bromo-2-methoxyethane (4.16 g, 30 mmol) was added to this mixture.After stirring at 50° C. for additional 16 hours, when TLC showedapproximately one third of starting material was converted into product,the reaction mixture was cooled, quenched with ice water (10 mL),extracted with EtOAc (10 mL*3). The combined organic layers were driedover anhydrous sodium sulfate, filtered and concentrated. The residuewas purified by column chromatography on silica gel (PE:EA=15:1). Thestarting material was recovered, and the procedure was repeated threetimes using the recovered starting material under same condition toafford A20 (total yield: 0.5 g, 42.6%) as light yellow oil. LCMSR_(t)=1.274 min in 2 min chromatography, 30-90AB, purity 79.4%, MS ESIcalcd. for C₂₅H₄₃O₃[M+H]⁺ 391, found 373 ([M+H−18]⁺).

Step 2. Preparation of compound A21. To a solution of A20 (0.5 g, 1.28mmol) in dry THF (5 mL) under nitrogen at 0 C was added borane-dimethylsulfide (1.28 mL, 12.8 mmol) dropwise. After stirring at 25° C. for 16hours, when TLC (PE:EA=5:1) showed the starting material was consumed,aqueous NaOH (10%, 10 mL) was added to this mixture dropwise at 0° C. Tothis mixture was added hydrogen peroxide (30%, 4.33 g, 38.4 mmol). Theresultant suspension was stirred at 25° C. for 1 hour. TLC (PE:EA=5:1)showed the intermediate was consumed. The reaction mixture was quenchedwith aqueous Na₂S₂O₃ (10 mL), extracted with EtOAc (10 mL*3). Thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated to give A21 (0.7 g, 77.5%, purity:58%) as light yellow oilwhich was used directly without further purification. LCMS t_(R)^(=1.027) min in 2 min chromatography, 30-90AB, purity 58.8%, MS ESIcalcd. for C₂₅H₄₅O₄[M+H]⁺ 409, found 431 ([M+Na]⁺).

Step 2. Preparation of compound 9. To solution of A21 (0.7 g, 0.991mmol, purity: 58%) in dichloromethane (15 mL) was added silica gel (1 g)and PCC (1.06 g, 4.95 mmol). After stirring at 25° C. for 16 hours, whenTLC (PE:EA=5:1) showed the starting material was consumed, the mixturewas filtered, and the filtrated was concentrated. The residue waspurified by column chromatography on silica gel (PE:EA=15:1) to givecompound 9 (0.3 g, 74.4%) as white solid. The product was divided intotwo batches; one batch (0.2 g) was used in next step without furtherpurification, and another one (0.1 g) was purified by prep.HPLC toafford pure product (27 mg) for delivery. ¹H NMR (400 MHz, CDCl₃) δ=3.58(d, J=9.6 Hz, 1H), 3.51 (s, 4H), 3.45 (d, J=10.0 Hz, 1H), 3.35 (s, 3H),2.53 (t, J=8.8 Hz, 1H), 2.20-2.15 (m, 1H), 2.11 (s, 3H), 2.07-1.97 (m,2H), 1.72-1.60 (m, 6H), 1.54-1.47 (m, 4H), 1.37-1.25 (m, 3H), 1.21-1.06(m, 8H), 1.01-0.91 (m, 1H), 0.86-0.79 (m, 1H), 0.62 (s, 3H). LCMSt_(R)=1.038 min in 2 min chromatography. 30-90AB, purity 100%, MS ESIcalcd. for C₂₅H₄₃O₄[M+H]⁺ 407, found 429 ([M+Na]⁺).

Example 10. Preparation of 10

Step 1. Preparation of compound B26. To a solution of B25 (2 g, 6.28mmol) in THF (30 mL) in a flask was added CsF (953 mg, 6.28 mmol) at 0°C., then TMSCF₃ (1.33 g, 9.42 mmol) was added dropwise. The reaction wasallowed to warm to 25° C. and stirred for 2 h. TLC(PE:EtOAc=3:1) showedthe starting material was consumed completely. Then the reaction mixturewas treated with 2M aq·HCl (10 mL) and stirred for 6 h. The reaction wasthen diluted with H₂O (30 mL) and extracted with EtOAc (30 mL×2). Thecombined organic layer was washed with brine (20 mL), dried over Na₂SO₄and concentrated to get the crude product which was purified by silicagel column (PE:EtOAc=50:1 to 10:1) to afford product B26 (1.1 g, 45.0%yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 3.49 (d, J=8.0 Hz,1H), 3.32-3.22 (m, 4H), 2.46-2.39 (m, 1H), 2.10-1.71 (m, 8H), 1.68-1.10(m, 14H), 0.85 (s, 3H).

Step 2. Preparation of compound B27. To a solution ofethyltriphenylphosphonium bromide (5.19 g, 14.0 mmol) in THF (30 mL),was added t-BuOK (1.57 g, 14.0 mmol). The reaction mixture was heated to60° C. for 1 h and B26 (1.1 g, 2.83 mmol) was added to the mixture whichwas stirred at 60° C. for an additional 8 h. TLC (PE:EtOAc=3:1) showedthe reaction was complete. The reaction mixture was cooled, then dilutedwith H₂O (30 mL) and extracted with EtOAc (30 mL×2). The combinedorganic layer was washed with brine (20 mL), dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel column(PE:EtOAc=100:1 to 15:1) to afford B27 (1 g, 88.6% yield) as a yellowoil. ¹H NMR (400 MHz, CDCl₃) δ 5.15-5.02 (m, 1H), 3.56 (d, J=8.0 Hz,1H), 2.46-2.39 (m, 1H), 3.34 (s, 3H), 3.29 (d, J=8.0 Hz, 1H), 2.43-1.80(m, 7H), 1.58-1.10 (m, 19H), 0.90 (s, 3H).

Step 3. Preparation of compound B28. To a solution of B27 (1 g, 2.49mmol) in THF (15 mL) under N₂ protection was added dropwise a solutionof BH₃-Me₂S (2.48 mL, 10 M) at 0° C. The solution was stirred at 25° C.for 4 h. TLC (PE/EtOAc=3/1) showed the reaction was complete. Aftercooling to 0° C., a solution of NaOH (9.93 mL, 3M) was added veryslowly, a large amount of gas released. After the addition was complete,H₂O₂ (4.53 mL, 33%) was added slowly and the inner temperature wasmaintained below 10° C. The resulting solution was stirred at 25° C. for1 h. The resulting solution was extract with EtOAc (20 mL×3). Thecombined organic solution was washed with saturated aqueous Na₂S₂O₃ (20mL×3), brine (20 mL), dried over Na₂SO₄ and concentrated in vacuum togive the crude product (1 g) as yellow oil. The crude product was usedfor the next step without further purification.

Step 4. Preparation of compound 10. A mixture of B28 (1.0 g, 2.38 mmol),PCC (0.767 g, 3.56 mmol) and silica gel (0.843 g, w/w=1/1.1) in DCM (15mL) was stirred at 25° C. for 2 h, the reaction mixture color becamebrown. TLC (PE/EtOAc=3/1) showed the reaction was complete. The solutionwas filtered and the filter cake was washed with DCM (20 mL). Thecombined filtrate was concentrated in vacuum. The residue was purifiedby silica gel column eluted with PE:EtOAc=15:1 to 8:1 to give compound10 (800 mg, 80.6%) as a white solid. MS ESI calcd. for C₂₄H₄₁O₄[M+H]⁺417, found 399 ([M+H−18]⁺). ¹H NMR (400 MHz, CDCl₃) δ 3.52 (d, J=8.0 Hz,1H), 3.33 (s, 3H), 3.28 (d, J=8.0 Hz, 1H), 2.58-2.52 (m, 1H), 2.20-1.60(m, 15H), 1.53-1.10 (m, 11H), 0.62 (s, 3H).

Example 11. Preparation of 11

Step 1. Preparation of compound B29. To a solution of Me₃SOI (691 mg,3.14 mmol) in THF (15 mL) in a flask was added t-BuOK (352 mg, 3.14mmol). The reaction mixture was stirred at 60° C. for 1.5 h. Then asolution of B25 (200 mg, 0.63 mmol) in THF (10 mL) was added to thereaction. The reaction was stirred for 0.5 h at 30° C. After theTLC(PE:EA=3:1) showed the reaction was complete, the reaction wasquenched with aq·NH₄Cl (30 mL). The reaction was extracted with EtOAc(20 mL×2), washed with brine (20 mL), dried over Na₂SO₄ and evaporatedin vacuum to afford crude product B29 (200 mg, 96% yield) as yellowsolid. ¹H NMR (400 MHz, CDCl₃) δ 3.52 (d, J=8.0 Hz, 1H), 3.36 (d, J=8.0Hz, 1H), 3.32 (s, 3H), 2.67-2.60 (m, 2H), 2.50-2.28 (m, 2H), 2.20-2.03(m, 2H), 1.98-1.70 (m, 8H), 1.52-1.02 (m, 10H), 0.86 (s, 3H).

Step 2. Preparation of compound B30. To a solution of B29 (200 mg, 0.602mmol) in MeOH (10 mL) in a flask was added MeONa (98 mg, 1.806 mmol),the reaction mixture was then heated to 60° C. and stirred for 6 h. TLC(PE:EtOAc=3:1) showed the reaction was complete. The reaction mixturewas then concentrated. The residue was purified by silica gel column(PE:EtOAc=10:1 to 5:1) to afford product B30 (150 mg, 68% yield) aswhite solid. ¹H NMR (400 MHz, CDCl₃) δ 3.52 (d, J=8.0 Hz, 1H), 3.38 (s,3H), 3.33 (s, 3H), 3.31 (d, J=8.0 Hz, 1H), 3.20 (s, 2H), 2.48-2.40 (m,2H), 2.20-2.01 (m, 2H), 1.98-1.60 (m, 8H), 1.58-1.10 (m, 11H), 0.85 (s,3H).

Step 3. Preparation of compound B31. To a solution ofethyltriphenylphosphonium bromide (6.08 g, 16.4 mmol) in THF (30 mL),was added t-BuOK (1.84 g, 16.4 mmol). The reaction mixture was heated to60° C. for 1 h and B30 (1.2 g, 3.29 mmol) was added to the mixture whichwas stirred at 60° C. for an additional 8 h. The reaction mixture wascooled, then diluted with H₂O (30 mL) and extracted with EtOAc (30mL×2). The combined organic layer was washed with brine (20 mL), driedover Na₂SO₄ and concentrated. The residue was purified by silica gelcolumn (PE:EtOAc=50:1 to 15:1) to afford product B31 (1.1 g, 88.7%yield) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 5.12-5.01 (m, 1H), 3.54(d, J=8.0 Hz, 1H), 3.36 (s, 3H), 3.32 (s, 3H), 3.26 (d, J=8.0 Hz, 1H),3.18 (s, 2H), 2.36-2.10 (m, 4H), 1.86-1.65 (m, 2H), 1.52-1.01 (m, 16H),0.85 (s, 3H).

Step 4. Preparation of compound B32. To a solution of B31 (1 g, 2.65mmol) in THF (30 mL) was added dropwise a solution of BH₃-Me₂S (2.65 mL,10 M) at 0° C. The solution was stirred at 25° C. for 4 h. TLC(PE:EtOAc=3:1) showed the reaction was almost complete. After cooling to0° C., a solution of NaOH (10.6 mL 3M) was added very slowly. After theaddition was complete, H₂O₂ (4.82 mL, 33%) was added slowly and theinner temperature was maintained below 10° C. The resulting solution wasstirred at 25° C. for 2 h. The resulting solution was extract with EtOAc(20 mL×3). The combined organic solution was washed with saturatedaqueous Na₂S₂O₃ (30 mL×3), brine (30 mL), dried over Na₂SO₄ andconcentrated in vacuum to give the crude product (1.1 g) as yellowsolid. The crude product was used for the next step without furtherpurification.

Step 5. Preparation of compound 11. A mixture of B32 (1.0 g, 2.53 mmol),PCC (0.816 g, 3.79 mmol) and silica gel (0.897 g, w/w=1/1.1) in DCM (15mL) was stirred at 30° C. for 2 h, the reaction mixture color becamebrown. TLC (PE/EtOAc=3/1) showed the reaction was complete. The solutionwas filtered and the filter cake was washed with DCM (20 mL). Thecombined filtrate was concentrated in vacuum. The residue was purifiedby silica gel column eluted with PE/EtOAc=15/1 to 5/1 to give compound11 (850 mg, 85.3%) as white solid. MS ESI calcd. for C₂₄H₄₁O₄[M+H]⁺ 393,found 375 ([M+H−18]⁺). ¹H NMR (400 MHz, CDCl₃) δ 3.52 (d, J=8.0 Hz, 1H),3.40 (s, 3H), 3.33 (s, 3H), 3.28 (d, J=8.0 Hz, 1H), 3.22 (s, 2H), 2.53(t, J₁=16.0 Hz, J₂=8.0 Hz, 1H), 2.18-2.10 (m, 5H), 2.05-1.95 (m, 2H),1.85-1.30 (m, 11H), 1.20-1.01 (m, 8H), 0.61 (s, 3H).

Example 12. Preparation of 13

Step 1. Preparation of compound B37. To a solution of PPh₃EtBr (3.18 g,8.58 mmol) in THF (15 mL) was added t-BuOK (962 mg, 8.58 mmol) at 25° C.After stirring at 60° C. for 1 h, a solution of 12 (1 g, 2.86 mmol) inTHF (5 mL) was added drop wise at 60° C. Then the reaction mixture wasstirred at 60° C. for 16 hrs. TLC (PE/EtOAc=5/1) showed the reaction wascomplete. The mixture was poured into ice-water (100 mL) and extractedwith EA (50 mL*2). The organic layer was washed with brine (50 mL),dried over Na₂SO₄ and filtered, concentrated in vacuum. The residue waspurified by silica gel column eluted with PE/EtOAc=15/1 to afford B37 (1g, Purity: 80%, Yield: 77.6%) as a white solid.

¹H NMR CDCl3 Bruker_P_400 MHz δ 5.18-4.99 (m, 1H), 3.83-3.71 (m, 1H),3.30 (s, 3H), 2.45-2.09 (m, 3H), 2.01-1.81 (m, 3H), 1.68-1.58 (m, 6H),1.58-1.37 (m, 10H), 1.31-1.12 (m, 14H), 1.08-1.03 (m, 3H), 0.91 (s, 3H).

Step 2. Preparation of compound B38. To a solution of B37 (1 g, 2.77mmol) in THF (20 mL) was added drop wise a solution of BH₃-Me₂S (2.77mL, 27.7 mmol) at 0° C. The solution was stirred at 25° C. for 16 hrs.TLC (PE/EtOAc=2/1) showed a new spot was obtained and a little materialwas remained. After cooling to 0° C., a solution of NaOH (9.23 mL, 3M)was added very slowly. After the addition was complete, H₂O₂ (4.5 mL,33%) was added slowly and the inner temperature was maintained below 10°C. The resulting solution was stirred at 25° C. for 2 hrs. TLC(PE/EtOAc=2/1) showed the reaction was complete. The resulting solutionwas extract with EtOAc (20 mL*2). The combined organic layer was washedwith saturated aqueous Na₂S₂O₃ (50 mL×2), brine (50 mL), dried overNa₂SO₄, filtered and concentrated in vacuum to give B38 (0.9 g, crude)as a white solid. The crude product was used for the next step withoutfurther purification.

Step 3. Preparation of compound 13. To a solution of B38 (800 mg, 2.11mmol) in DCM (10 mL) was added PCC (907 mg, 4.22 mol) at 25° C. Themixture was stirred at 25° C. for 2 hrs. TLC showed the reaction wascomplete. The solution was filtered and the filter cake was washed withDCM (50 mL*2). The combined filtrate was concentrated in vacuum. Theresidue was purified by silica gel column eluted with(PE/EtOAc=5/1) toafford 13 (600 mg, Purity: 90%, Yield: 68%) as a white solid. The 13(100 mg, Purity: 90%) was purified by prep. HPLC (25° C.,column:DuraShell 150*25 mm*5 um, gradient: 48-78% B, 10 mM NH₄HCO₃-ACN),flow rate: 25 mL/min) to give 13 (10 mg, Purity: 100%, Yield: 10.0%) aswhite solid.

¹H NMR CDCl3 Bruker_P_400 MHz δ 3.78-3.74 (m, 1H), 3.27 (s, 3H),2.56-2.51 (m, 1H), 2.22-2.16 (m, 1H), 2.12 (s, 3H), 2.06-1.94 (m, 2H),1.91-1.79 (m, 1H), 1.74-1.61 (m, 6H), 1.50-1.32 (m, 6H), 1.29-1.10 (m,10H), 1.09-1.02 (m, 3H), 0.64 (s, 3H) LCMS Rt=1.067 min in 2.0 minchromatography, 30-90 AB, purity 100%, MS ESI calcd. For C₂₄H₄₀O₃[M+H−H₂O-MeOH]⁺ 327, found 327.

Example 13. Preparation of 14

Step 1. Preparation of compound A4. To a solution of C10 (15.0 g, 46.81mmol) in DCM (300 mL) was added PCC (15.1 g, 70.2 mmol), followed bysilica gel (25 g). The reaction mixture was stirred at 25° C. for 3hours. When TLC (stained with PMA) showed that the reaction completed,the reaction mixture was filtered through a pad of celite and thefiltrate was concentrated under reduced pressure to afford crude productas brown oil, which was purified by column chromatography on silica gel(eluted with Petroleum ether/EtOAc=3:1) to afford desired product asyellow solid (15 g, 100% yield).

¹H NMR (400 MHz, CDCl₃) δ 3.69-3.59 (m, 2H), 3.32 (s, 3H), 2.55-2.36 (m,4H), 2.34-2.23 (m, 1H), 2.19-2.02 (m, 2H), 1.98-1.76 (m, 4H), 1.67-1.44(m, 3H), 1.42-1.33 (m, 2H), 1.31-1.14 (m, 4H), 1.07-0.94 (m, 1H), 0.89(s, 3H), 0.85-0.75 (m, 1H).

Step 2. Preparation of compound C11. To a suspension of Me₃SOI (4.13 g,12.5 mmol, 1.5 eq) in THF (110 mL) was added tBuOK (2.8 g, 25.0 mmol,2.0 eq). The reaction mixture was stirred at 25° C. for 1 hour. Thensolution of A4 (4.0 g, 12.5 mmol, 1.0 eq) in THF (10 mL) was added tothe reaction mixture and stirred for 5 hours. When TLC (Petroleumether/EtOAc=3:1, stained with PMA) showed that the reaction completed,the reaction mixture was quenched with sat·aq·NH₄Cl (150 mL), extractedwith EtOAc (100 mL*2). The combined organic layer was washed with brine(150 mL), dried over Na₂SO₄ and concentrated under reduced pressure toafford the desired product as colorless oil (4.0 g, crude), which wasused in next step without further purification.

Step 3. Preparation of compound C12. To a solution of C11 (4.0 g, 12.1mmol) in MeOH (150 mL) was added MeONa (1.95 g, 36.1 mmol). The reactionmixture was heated to 60° C. and stirred for 5 hours. When TLC showedthat the reaction completed, the reaction mixture was concentrated underreduced pressure to remove most of the solvent. The residue wasdissolved with EtOAc (200 mL), washed with H₂O (100 mL) and brine (100mL), dried over Na2SO4 and concentrated under reduced pressure to affordcrude product as brown oil, which was purified by column chromatographyon silica gel (eluted with Petroleum ether/EtOAc=3:1) to afford desiredproduct as colorless oil (2.4 g, 55% yield, 2 Steps).

¹H NMR (400 MHz, CDCl₃) δ 3.49 (d, J=10.2 Hz, 1H), 3.41-3.34 (m, 4H),3.29 (s, 3H), 3.20 (s, 2H), 2.43 (dd, J=19.2, 8.6 Hz, 1H), 2.13-1.88 (m,4H), 1.83-1.67 (m, 5H), 1.55-1.33 (m, 5H), 1.27-1.12 (m, 6H), 1.08-0.97(m, 1H), 0.91-0.80 (m, 4H).

Step 4. Preparation of compound C13. To a solution of CH₃CH₂PPh₃Br (7.31g, 19.7 mmol, 3.0 eq) in THF (20 mL) was added tBuOK (2.21 g, 19.7 mmol,3.0 eq) at 25° C., after addition, the reaction mixture was heated to60° C. and stirred for 1 hour. Then C12 (2.4 g, 1.0 eq) was added andthe reaction mixture was stirred at this temperature for 16 hours. WhenTLC showed that the reaction completed, the reaction mixture was pouredinto H₂O (50 mL), extracted with EtOAc (50 mL*2). The combined organiclayer was washed with brine (50 mL), dried over Na₂SO₄ and concentratedunder reduced pressure to afford crude product as brown oil, which waspurified by column chromatography on silica gel (eluted with Petroleumether/EtOAc=10:1) to afford desired product C13 as colorless oil(1.67 g,80.2%).

¹H NMR (400 MHz, CDCl₃) δ 5.07-5.14 (m, 1H), 3.48 (d, J=10.0 Hz, 1H),3.41-3.35 (m, 4H), 3.29 (s, 3H), 3.20 (s, 2H), 2.41-2.08 (m, 3H),1.99-2.02 (m, 1H), 1.78-1.57 (m, 9H), 1.55-1.30 (m, 6H), 0.73-1.22 (m,10H).

Step 5. Preparation of compound C14. Borane-tetrahydrofuran complex(15.3 mL, 15.3 mmol, 1.0 M solution in THF) was added to a solution ofC13 (1.67 g, 4.43 mmol) in anhydrous tetrahydrofuran (20 mL) at roomtemperature under nitrogen, after which the mixture was stirred for 1 h.The mixture was cooled in an ice bath and 10% aqueous sodium hydroxidesolution (8.8 mL) was added, followed by 30% aqueous hydrogen peroxidesolution (8.8 mL). The resulting mixture was stirred at room temperaturefor 1 h and then extracted with ethyl acetate (3×50 mL). The combinedorganic extracts were washed sequentially with 10% aqueous sodiumsulfite and saturated aqueous sodium chloride solutions, dried withsodium sulfate and filtered. The solvents were removed under reducedpressure to provide crude C14 as a colorless oil that was used in thenext step without further purification (1.77 g, crude).

Step 6. Preparation of compound 14. To a solution of C14 (1.77 g, 4.48mmol) in CH₂Cl₂ (20 mL) was added silica gel (2.55 g). Then the PCC(1.44 g, 6.72 mmol) was added. The mixture was stirred at 25° C. for 16hours. TLC showed the reaction was completed. The mixture was filtered.The solution was extracted with EtOAc (20 mL*3) and dried over Na₂SO₄.The combined organic layer was concentrated under vacuum and purified bycolumn chromatography on silica gel (PE:EA=10:1) to give 14 (1.5 g) as awhite solid.

¹H NMR (400 MHz, CDCl₃) δ 3.46 (d, J=10.0 Hz, 1H), 3.41-3.34 (m, 4H),3.28 (s, 3H), 3.20 (s, 2H), 2.53 (t, J=8.9 Hz, 1H), 2.22-1.94 (m, 7H),1.75-1.61 (m, 5H), 1.55-0.80 (m, 14H), 0.62 (s, 3H). LCMS t_(R)^(=1.978) min in 2 min chromatography, 10-80AB_E, purity 100%, MS ESIcalcd. for C₂₄H₄₀O₄ [M+H−H₂O-2MeOH]⁺ 311, found 311.

Assay Methods

Compounds provided herein can be evaluated using various assays;examples of which are described below.

Steroid Inhibition of TBPS Binding

[35S]-t-Butylbicyclophosphorothionate (TBPS) binding assays using ratbrain cortical membranes in the presence of 5 μM GABA has been described(Gee et al, J. Pharmacol. Exp. Ther. 1987, 241, 346-353; Hawkinson etal, Mol. Pharmacol. 1994, 46, 977-985; Lewin, A. H et al., Mol.Pharmacol. 1989, 35, 189-194).

Briefly, cortices are rapidly removed following decapitation of carbondioxide-anesthetized Sprague-Dawley rats (200-250 g). The cortices arehomogenized in 10 volumes of ice-cold 0.32 M sucrose using aglass/teflon homogenizer and centrifuged at 1500×g for 10 min at 4° C.The resultant supernatants are centrifuged at 10,000×g for 20 min at 4°C. to obtain the P2 pellets. The P2 pellets are resuspended in 200 mMNaCl/50 mM Na—K phosphate pH 7.4 buffer and centrifuged at 10,000×g for10 min at 4° C. This washing procedure is repeated twice and the pelletsare resuspended in 10 volumes of buffer. Aliquots (100 μL) of themembrane suspensions are incubated with 3 nM [³⁵S]-TBPS and 5 μLaliquots of test drug dissolved in dimethyl sulfoxide (DMSO) (final0.5%) in the presence of 5 μM GABA. The incubation is brought to a finalvolume of 1.0 mL with buffer. Nonspecific binding is determined in thepresence of 2 μM unlabeled TBPS and ranged from 15 to 25%. Following a90 min incubation at room temp, the assays are terminated by filtrationthrough glass fiber filters (Schleicher and Schuell No. 32) using a cellharvester (Brandel) and rinsed three times with ice-cold buffer. Filterbound radioactivity is measured by liquid scintillation spectrometry.Non-linear curve fitting of the overall data for each drug averaged foreach concentration is done using Prism (GraphPad). The data are fit to apartial instead of a full inhibition model if the sum of squares issignificantly lower by F-test. Similarly, the data are fit to a twocomponent instead of a one component inhibition model if the sum ofsquares is significantly lower by F-test. The concentration of testcompound producing 50% inhibition (IC₅₀) of specific binding and themaximal extent of inhibition (I_(max)) are determined for the individualexperiments with the same model used for the overall data and then themeans±SEM.s of the individual experiments are calculated. Picrotoxinserves as the positive control for these studies as it has beendemonstrated to robustly inhibit TBPS binding.

Various compounds are or can be screened to determine their potential asmodulators of [³⁵S]-TBPS binding in vitro. These assays are or can beperformed in accordance with the above discussed procedures.

Patch clamp electrophysiology of recombinant α₁β₂γ₂ and α₄β3δ GABA_(A)receptors

Cellular electrophysiology is used to measure the pharmacologicalproperties of our GABA_(A) receptor modulators in heterologous cellsystems. Each compound is tested for its ability to affect GABA mediatedcurrents at a submaximal agonist dose (GABA EC₂₀=2 μM). LTK cells arestably transfected with the α₁β₂γ₂ subunits of the GABA receptor and CHOcells are transiently transfected with the α₄β3δ subunits via theLipofecatamine method. Cells were passaged at a confluence of about50-80% and then seeded onto 35 mm sterile culture dishes containing 2 mlculture complete medium without antibiotics or antimycotics. Confluentclusters of cells are electrically coupled (Pritchett et al., Science,1988, 242, 1306-1308.). Because responses in distant cells are notadequately voltage clamped and because of uncertainties about the extentof coupling (Verdoorn et al., Neuron 1990, 4, 919-928.), cells werecultivated at a density that enables the recording of single cells(without visible connections to other cells).

Whole cell currents were measured with HEKA EPC-10 amplifiers usingPatchMaster software or by using the high throughput QPatch platform(Sophion). Bath solution for all experiments contained (in mM): NaCl 137mM, KCl 4 mM, CaCl₂ 1.8 mM, MgCl₂ 1 mM, HEPES 10 mM, D-Glucose 10 mM, pH(NaOH) 7.4. In some cases 0.005% cremophor was also added. Intracellular(pipette) solution contained: KCl 130 mM, MgCl₂ 1 mM, Mg-ATP 5 mM, HEPES10 mM, EGTA 5 mM, pH 7.2. During experiments, cells and solutions weremaintained at room temperature (19° C.-30° C.). For manual patch clamprecordings, cell culture dishes were placed on the dish holder of themicroscope and continuously perfused (1 ml/min) with bath solution.After formation of a Gigaohm seal between the patch electrodes and thecell (pipette resistance range: 2.5 MΩ-6.0 MΩ; seal resistance range:>1GΩ) the cell membrane across the pipette tip was ruptured to assureelectrical access to the cell interior (whole-cell patch-configuration).For experiments using the QPatch system, cells were transferred assuspension to the QPatch system in the bath solution and automated wholecell recordings were performed.

Cells were voltage clamped at a holding potential of −80 mV. For theanalysis of test articles, GABA receptors were stimulated by 2 μM GABAafter sequential pre-incubation of increasing concentrations of the testarticle. Pre-incubation duration was 30 s and the duration of the GABAstimulus was 2s. Test articles were dissolved in DMSO to form stocksolutions (10 mM). Test articles were diluted to 0.01, 0.1, 1, and 10 μMin bath solution. All concentrations of test articles were tested oneach cell. The relative percentage potentiation was defined as the peakamplitude in response to GABA EC₂₀ in the presence of the test articledivided by the peak amplitude in response to GABA EC₂₀ alone, multipliedby 100.

TABLE 1 TBPS binding of the exemplary compounds. Name TBPS IC₅₀ (nM) 1 C2 C 3 B 4 A 5 A 6 B 7 E 8 E 9 D 10 C For Table 1: TBPS: A” indicates anIC₅₀ < 10 nM, “B” indicates an IC₅₀ 10 to < 50 nm, “C” indicates an IC₅₀50 nM to < 100 nM, “D” indicates an IC₅₀ 100 nM to < 500 nM, and “E”indicates IC₅₀ greater than or equal to 500 nM.

TABLE 2 Electrophysiological evaluation of the exemplary compounds atGABA_(A)-R. GABA (α1β2γ2) GABA (α4β3δ) Manual Qpatch in Ltk, patch inCHO, Name % efficacy at 10 μM % efficacy at 10 μM 1 B C 2 C D 5 C C 6 BD For Table 2. GABAA receptors α1ß2γ2 and α4ß3δ % efficacy: “A” 10-100,“B” >100-500, “C” >500; D indicates the data is not available or has notbeen determined.

Other Embodiments

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

We claim:
 1. A method for treating a CNS-related disorder in a humansubject in need thereof comprising administering to the human subject atherapeutically effective amount of a) a compound of Formula (I) or apharmaceutically acceptable salt thereof or b) a pharmaceuticalcomposition comprising a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable excipient,wherein:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, carbocyclyl, or heterocyclyl; eachof R^(2a) and R^(2b) is independently hydrogen, C₁-C₆ alkyl, halo,cyano, —OR^(A), or —NR^(B)R^(C), or R^(2a) and R^(2b) together with thecarbon atom to which they are attached form a ring; R³ is hydrogen,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, carbocyclyl, heterocyclyl,aryl, heteroaryl, —C(O)R^(A), —C(O)OR^(A), or —C(O)NR^(B)R^(C);

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond; wherein when the

between —CR⁶ and —CR^(5a)R^(5b) is a double bond, then one of R^(5a) orR^(5b) is absent; and when one of the

is a double bond, R⁶ is absent; each of R^(5a) and R^(5b) isindependently absent, hydrogen, C₁-C₆ alkyl, or halo; R⁶ is absent orhydrogen; Z is —CR^(7a)R^(7b)—, wherein each of R^(7a) and R^(7b) isindependently hydrogen or C₁-C₆ alkyl, or R^(7a) and R^(7b), togetherwith the carbon atom to which they are attached, form a ring; R^(A) ishydrogen, C₁-C₆ alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl;each of R^(B) and R^(C) is independently hydrogen, C₁-C₆ alkyl,carbocyclyl, heterocyclyl, aryl, heteroaryl, or taken together with theatom to which they are attached form a ring. 2-34. (canceled)